Opioid agonist/antagonist combinations

ABSTRACT

The invention is directed in part to oral dosage forms comprising a combination of an orally analgesically effective amount of an opioid agonist and an orally active opioid antagonist, the opioid antagonist being included in a ratio to the opioid agonist to provide a combination product which is analgesically effective when the combination is administered orally, but which is aversive in a physically dependent subject. Preferably, the amount of opioid antagonist included in the combination product provides at least a mildly negative, “aversive” experience in physically dependent addicts (e.g., precipitated abstinence syndrome).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/214,659, filed Mar. 14, 2014, which is a continuation of U.S. patentapplication Ser. No. 13/337,898, filed Dec. 27, 2011 (now U.S. Pat. No.8,673,355), which is a continuation of U.S. patent application Ser. No.12/785,957, filed May 24, 2010 (now U.S. Pat. No. 8,105,631,) which is acontinuation of U.S. patent application Ser. No. 12/220,760, filed Jul.28, 2008 (now U.S. Pat. No. 7,749,542), which is a continuation of U.S.patent application Ser. No. 11/645,401, filed Dec. 26, 2006 (now U.S.Pat. No. 7,419,686), which is a continuation of U.S. patent applicationSer. No. 10/694,559, filed Oct. 27, 2003 (now U.S. Pat. No. 7,172,767),which is a continuation of U.S. patent application Ser. No. 10/244,783,filed Sep. 16, 2002 (now U.S. Pat. No. 6,696,066), which is acontinuation of U.S. patent application Ser. No. 09/815,167, filed Mar.22, 2001 (now U.S. Pat. No. 6,475,494), which is a continuation of U.S.patent application Ser. No. 09/218,662, filed Dec. 22, 1998 (now U.S.Pat. No. 6,277,384), which claims priority and benefit to application ofU.S. Provisional Application Ser. No. 60/068,480, filed December Dec.22, 1997, hereby incorporated by reference.

BACKGROUND

Opioids, also known as opioid agonists, are a group of drugs thatexhibit opium or morphine-like properties. The opioids are employedprimarily as moderate to strong analgesics, but have many otherpharmacological effects as will, including drowsiness, respiratorydepression, changes in mood and mental clouding without a resulting lossof consciousness. Opioids act as agonists, interacting withstereospecific and saturable binding sites in the brain and othertissues. Endogenous opioid-like peptides are present particularly inareas of the central nervous system that are presumed to be related tothe perception of pain; to movement, mood and behavior, and to theregulation of neuroendocrinological functions. Opium contains more thantwenty distinct alkaloids. Morphine, codeine and papaverine are includedin this group.

By the middle of the nineteenth century, the use of pure alkaloids suchas morphine rather than crude opium preparations began to spreadthroughout the medical world. Parenteral use of morphine tended toproduce a more severe variety of compulsive drag use. The problem ofaddiction to opioids stimulated a search for potent analgesics thatwould be free of the potential to produce addiction. By 1967,researchers had concluded that the complex interactions amongmorphine-like drugs, antagonists, and what was then called “mixedagonist-antagonist” could best be explained by postulating the existenceof more than one type of receptor for opioids and related drugs. Withthe advent of new totally synthetic entities with morphine-like actions,the term opioid was generally retained as a generic designation for allexogenous substances that bind stereo-specifically to any of severalsubspecies of opioid receptors and produce agonist actions.

The potential for the development of tolerance and physical dependencewith repeated opioid use is a characteristic feature of all the opioiddrugs, and the possibility of developing psychological dependenceaddiction) is one of the major concerns in the use of the treatment ofpain with opioids, even though iatrogenic addiction is rare. Anothermajor concern associated with the use of opioids is the diversion ofthese drugs from the patient in pain to another (non-patient) forrecreational proposes, e.g., to an addict.

The overall abuse potential of an opioid is not established by any onesingle factor, Instead, there is a composite of factors, including, thecapacity of the drug to produce the kind of physical dependence in whichdrug withdrawal causes sufficient distress to bring about drug-seekingbehavior, the ability to suppress withdrawal symptoms caused bywithdrawal from other agents; the degree to which it induces euphoriasimilar to that produced by morphine and other opioids; the patterns oftoxicity that occur when the drug is dosed above its normal therapeuticrange; and physical characteristics of the drugs such as watersolubility. Such physical characteristics may determine whether the drugis likely to be abused, by the parenteral route.

In the United States, the effort to control the compulsive drug userincludes efforts to control drug availability by placing restrictions onthe use of opioids in the treatment of pain of compulsive drug users. Inpractice, the physician is often faced with a choice of administeringpotent opioid analgesics even to persons who seem predisposed to developpsychological dependence, i.e., addiction, on such drugs. In view ofthis problem, it has been recommended that these patients should not begiven an opioid when another drug without a potential for abuse willsuffice; and further that these, patients should not be permitted toself-administer such drugs parenterally and should only be given a fewdays' supply at a time.

At least three basic patterns of opioid use and dependence have” beenidentified. The first involves individuals whose drug use begins in thecontext of medical treatment and who obtain their initial suppliesthrough, e.g., physicians. Mother pattern begins with experimental or“recreational” drug use and progresses to more intensive use. A thirdpattern involves users who begin in one or another of the preceding waysbut later switch to oral opioids such as methadone, obtained fromorganized addiction treatment programs.

Tolerance refers to the need to increase the dose of opioid over aperiod of time in order to achieve the same level of analgesia oreuphoria, or the observation that repeated administration of the samedose results in decreased analgesia, euphoria, or other opioid effects.It has been found that a remarkable degree of tolerance develops to therespiratory depressant, analgesic, sedative, emetic and euphorigeniceffects of opioids. However, the rate at which this tolerance maydevelop in either an addict or in a patient requiring treatment of pain,depends on the pattern of use. If the opioid is used frequently, it maybe necessary to increase the dose. Tolerance does not develop equally orat the same rate to all the effects of opioids, and even users who arehighly tolerant to respiratory depressant effects continue to exhibitmiosis and constipation. Tolerance to opioids largely disappears whenthe withdrawal syndrome has been completed.

Physical dependence may develop upon repeated administrations orextended use of opioids. Physical dependence is gradually manifestedafter stopping opioid use or is precipitously manifested (e.g., within20 minutes) after administration of a narcotic antagonist (referred to“precipitated withdrawal”). Depending upon the drug to which dependencehas been established and the duration of use and dose, symptoms ofwithdrawal vary in number and kind, duration and severity. The mostcommon symptoms of the withdrawal syndrome include anorexia, weightloss, papillary dilation, chills alternating with excessive sweating,abdominal ‘cramps, nausea, vomiting, muscle spasms, hyperirritability,lachrymation, rinorrhea, goose flesh and increased heart rate.Abstinence syndrome typically begins to occur 24-48 hours after the lastdose, and the syndrome reaches its maximum intensity about the third dayand may not begin to decrease until the third week.

Psychological dependence (i.e., addiction) on opioids is characterizedby drug-seeking behavior directed toward achieving euphoria and escapefrom, e.g., psychosocioeconomic pressures. An addict will continue toadminister opioids for non-medicinal purposes and in the face ofself-harm.

Pharmacologically, opioid antagonists typically block or reverse all ofthe effect of opioid agonists. One use of opioid antagonists is as aonce-a-day treatment of naltrexone to block euphoric effects that mightbe otherwise obtained upon administration of opioids to addicts. Smalldoses of opioid antagonists have been used to determine whetherindividuals are physically dependent on opioids. Most commonly, opioidantagonists are used to reverse the effects of opioids on individualswho have overdosed on opioid agonist drugs.

There have previously been attempts in the art to control the abusepotential associated with opioid analgesics, Typically, a particulardose of an opioid analgesic is more potent when administeredparenterally as compared to the same dose administered orally,Therefore, one popular mode of abuse of oral medications involves theextraction of the opioid from the dosage form, and the subsequentinjection of the opioid (using any “suitable” vehicle for injection) inorder to achieve a “high.” Attempts to curtail abuse have thereforetypically centered around the inclusion in the oral dosage form of anopioid antagonist which is not orally active but which willsubstantially block the analgesic effects of the opioid if one attemptsto dissolve the opioid and administer it parenterally.

For example, the combination of peritazocine and naloxone has beenutilized in tablets available in the United States, commerciallyavailable as Talwin®Nx from Sanofi-Winthrop. Talwin®Nx containspentazocine hydrochloride equivalent to 50 mg base and naloxonehydrochloride equivalent to 0.5 mg base. Talwin®NX is indicated for therelief of moderate to severe pain. The amount of naloxone present inthis combination has no action when taken orally, and will not interferewith the pharmacologic action of pentazocine. However, this amount ofnaloxone given by injection has profound antagonistic action to narcoticanalgesics. Thus, the inclusion of naloxone is intended to curb a formof misuse of oral pentazocine which occurs when the dosage form issolubilized and injected. Therefore, this dosage has lower potential forparenteral misuse than previous oral pentazocine formulations. However,it is still subject to patient misuse and abuse by the oral route, forexample, by the patient taking multiple doses at once.

Sunshine, et al. “Analgesic Efficacy of Pentazocine Versus aPentazocine-Naloxone Combination Following Oral Administration”, Clin.J. Pain, 1988:4:35-40, reported on the effect of the addition of 0.5 mgnaloxone on the analgesic efficacy of pentazocine 50 mg. The combinationwas found to be significantly less efficacious than pentazocine for thesum of the pain intensity difference (SPID), and for relief and painintensity difference (PID) at the fourth hour, For patients withmoderate baseline pain, the combination produced significantly less painrelief than pentazocine for SPID and for relief and PID at hours 3 and4. In patients with severe baseline pain, there was no significantdifference found between pentazocine and the combination of pentazocineplus naloxone.

Wang, et al. “Crossover and Parallel Study of Oral Analgesics”, J. Clin.Pharmacol 1981; 21:162-8, studied the combination of naloxone 0.25 mgand Percodan® (composed of 4.5 mg oxycodone HCl, oxycodone terephthalate0.28 mg, aspirin 224 mg, phenacetin 160 mg, and caffeine 32 mg) comparedto Percodan® alone, and placebo in a crossover study of patients withchronic pain. The combination had lower mean scores than Percodan® alonefor most of the analgesic hourly parameters in the later hours of thetrial. However, for the summary variables, the combination showed nosignificant difference from either placebo or Percodan®.

A fixed combination of buprenorphine and naloxone was introduced in 1991in New Zealand (Temgesic®Nx, Reckitt & Colman) for the treatment ofpain.

A fixed combination therapy comprising tilidine (50 mg) and naloxone (4mg) has been available in Germany for the management of severe painsince 1978 (Valoron®N, Goedecke). The rationale for the combination ofthese drugs is effective pain relief and the prevention of tilidineaddiction through naloxone-induced antagonisms at the morphine receptor.

U.S. Pat. No. 3,773,955 (Pachter, et al.) described orally effectiveanalgetic compositions which upon parenteral administration do notproduce analgesia, euphoria, or physical dependence, and thereby preventparenteral abuse of the analgetic agents. Such compositions containedfrom about 0.1 mg to about 10 mg naloxone per analgetic oral dose. Thisreference was not concerned with oral abuse of opioids.

U.S. Pat. No. 3,493,657 (Lewenstein, et al.) described compositionscomprising naloxone and morphine or oxymorphone, which compositions weresaid to provide a strong analgesic effect without the occurrence ofundesired side effects such as hallucinations.

U.S. Pat. No. 4A57,933 (Gordon, et al.) described a method fordecreasing both the oral and parenteral abuse potential of stronganalgetic agents such as oxycodone, propoxyphene and pentazocine, bycombining an analgesic dose of the opioid with naloxone in a specific,relatively narrow range. Oxycodone-naloxone compositions having a ratioof 2.5-5:1 parts by weight and pentazocine-naloxone compositions havinga ratio of 16-50:1 parts by weight were preferred. The dose of naloxonewhich was to be combined with the opioid is stated to substantiallyeliminate the possibility of either oral or parenteral abuse of theopioid without substantially affecting the oral analgesic activitythereof,

U.S. Pat. No. 4,582,835 (Lewis) describes a method of treating pain byadministering a sublingually effective dose of buprenorphine withnaloxone. Lewis describes dosage ratios of naloxone to buprenorphinefrom 1:3 to 1:1 for parenteral administration, and from 1:2 to 2:1 forsublingual administration.

It has been increasingly recognized in the art that oral opioidformulations are not only being abused by the parenteral route, but alsovia the oral route when the patient or addict orally self-administersmore than the prescribed oral dose during any dosage interval. There istherefore a need for the development of a formulation for the treatmentof pain which is administrable orally and which provides a lowerpotential for oral abuse.

To the inventors' knowledge, a ratio of opioid agonist to opioidantagonist which would be analgesically effective when the combinationis administered orally, but which is aversive in a physically dependentsubject has not been recognized to date.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of the invention to provide an. oral dosage form of anopioid analgesic which is subject to less abuse potential via the oralroute than prior commercially available dosage forms.

It is a further object of the present invention to provide an oraldosage form of an opioid analgesic and method which provides therapeuticanalgesia and which also provides a negative, “aversive” experience whena large amount of the opioid, e.g., about 2-3 times the usuallyprescribed dose, is taken by or administered to a physically dependentsubject.

It is a further object of the present invention to provide an oraldosage form of an opioid analgesic and a method for providingtherapeutic analgesia in a manner which is not as positively reinforcingin non physically dependent subjects taking more than the usuallyprescribed dose, e.g., about 2-3 times the usually prescribed dose ofthe opioid, as compared to the same amount of opioid without theantagonist.

It is a further object of the invention to provide a method of treatingpain in human patients with an oral dosage form of an opioid analgesicwhile reducing the oral abuse potential of dosage form.

It is a further object of the invention to provide a method ofmanufacturing an oral dosage form of an opioid analgesic such that ithas less oral abuse potential.

The above objects and others are achieved by the present invention,which is directed in part to the surprising finding that there exists aratio of opioid antagonist to opioid agonist (analgesic) which isanalgesically effective when the combination is administered orally, butwhich is aversive in a physically dependent subject. To the inventor'sknowledge, this was not even considered by those skilled in the art,e.g., an addictionologist, analgesiologist, a clinical pharmacologist.It is surprising that one combination product (of combinedantagonist/agonist) could in essence be therapeutic to one population(patients in pain), while being unacceptable (aversive) in a differentpopulation (e.g., physically dependent subjects) when administered atthe same dose or at a higher dose than the usually prescribed dosage,e.g., about 2-3 times the usually prescribed dose of the opioid.

The present invention is directed in part to an oral dosage formcomprising an orally analgesically effective amount of an opioid agonistand an opioid antagonist in a ratio which maintains analgesic efficacyby the opioid analgesic but which may decrease analgesia somewhat asassessed by direct measurement in patients or by the use of one or moresurrogate measures of opioid efficacy (analgesia) in human subjects.Surrogate measures of opioid efficacy (analgesia) include sedation,respiratory rate and/or pupil size (via pupillometry), and visualanalogue scale (“VAS”) for “drag effect”, Such surrogate measures areaffected in a direction which indicates reduced opioid effect, ascompared to the same dose of opioid without the concomitant dose ofopioid antagonist.

In certain preferred embodiments where the opioid is hydrocodone and theantagonist is naltrexone, the oral dosage form includes hydrocodone inthe form of its bitartrate salt and naltrexone in the form of itshydrochloride salt.

In certain preferred embodiments where the opioid, is hydrocodone andthe antagonist is naltrexone, the ratio of naltrexone to hydrocodone ispreferably from about 0.03-0.27:1 by weight, and more preferably frontabout 0.05-0.20:1 by weight.

The present invention is directed to a method of preventing oral abuseof an oral opioid formulation by a subject, comprising preparing an oraldosage form which comprises an orally analgesically effective amount ofan opioid agonist and an opioid antagonist in a ratio which maintainsanalgesic efficacy by the opioid analgesic but which rim decreaseanalgesia somewhat as assessed by direct measurement in patients or bythe use of one or more surrogate measures of wield effect in humansubjects. When the oral dosage form is taken by a physically dependentsubject at a relatively large dosage, e.g., about 2-3 times the usuallyprescribed dose, that use is aversive in a physically dependent humansubject and preferably not as positively reinforcing as the opioid(ingested alone) in anon-physically dependent human subject.

The present invention is also directed to a method of treatment,comprising orally administering au orally analgesically effective amountof an opioid agonist together with an opioid antagonist in a ratio whichmaintains analgesic efficacy by the opioid analgesic but which maydecrease analgesia somewhat by direct measurement in patients or by theuse of one or more surrogate measures of opioid effect in humansubjects.

The present invention is further directed in part to oral dosage formscomprising a combination of an orally analgesically effective amount ofan opioid agonist. and an orally active opioid antagonist, the opioidantagonist being included in an amount (1) which does not cause areduction in the level of analgesia elicited from the dosage form uponoral administration. to a non-therapeutic level and (ii) which providesat least a mildly negative, “aversive” experience in physicallydependent subjects (e.g., precipitated abstinence syndrome) when thesubjects attempt to take at least twice the usually prescribed dose at atime (and often 2-3 times that dose or more), as compared to acomparable dose of the opioid without the opioid antagonist present,Preferably, the amount of naltrexone included in the oral dosage form isless positively reinforcing (e.g., less “liked”) to a non-physicallydependent opioid addict than a comparable oral dosage form without theantagonist included. Preferably, the formulation provides effectiveanalgesia when orally administered.

For purposes of the present invention, the phrase “which may decreaseanalgesia somewhat as assessed by direct measurement in patients or bythe use of one or more surrogate measures of opioid analgesic efficacyin human subjects” means that the patient in pain may or may notappreciably notice the difference between the formulation administeredin accordance with the invention (i.e., combination of opioidagonist/antagonist) and a similar formulation which includes the samedose of opioid agonist without the opioid antagonist, but will obtain ananalgesic effect from the combination. The pharmacodynamic effect(analgesia) of the formulations administered in accordance with theinvention can be described by means of, for example, scores from ananalgesic questionnaire reported by the patients at serial timesfollowing administration of the dosage form. Summary measures ofanalgesia include the sum of pain intensity difference (SPID)) and totalpain relief (TOTPAR),

In certain preferred embodiments, the amount of opioid antagonistincluded in the dosage form may cause a clinically significant reductionin the level of analgesia elicited from the dosage form upon oraladministration, e.g., as measured by surrogate measures such as a VisualAnalogue Scale (“VAS”) for “drug effect”. In other embodiments, theamount of opioid antagonist included in the oral dosage form may cause anoticeable reduction in the level of analgesia elicited from the dosageform upon oral administration, but does not reduce the level ofanalgesia provided to a subtherapeutic level.

Preferably, the amount of antagonist included in the oral dosage form isless positively reinforcing (e.g., less “liked”) by a. non-physicallydependent opioid subject than a comparable oral dosage form without theantagonist included.

The present invention is also directed to a method of preparing an oraldosage form of an opioid analgesic intended for the treatment of pain inhuman patients in a manner which minimizes the likelihood of oral abuseof the dosage form, combining an orally analgesically effective amountof an opioid agonist together with an opioid antagonist in a ratio whichmaintains analgesic efficacy by the opioid analgesic but which maydecrease analgesia somewhat by direct measurement inpatients or by theuse of one or more surrogate measures of analgesia in human subjects. Incertain embodiments, the combination when orally administered provides aclinically significant reduction in the level of analgesia elicited fromthe dosage form upon oral administration (as compared to the same doseof opioid alone), and provides at least a mildly negative,′ “aversive”experience in a physically dependent subject (e.g., precipitatedabstinence syndrome) when the subject takes more than the usuallyprescribed or usual dose of opioid. The subject may be, for example, anaddict who attempts to achieve euphoria (a “high”) by taking more than(e.g., at least 2-3 times) the usually prescribed dose at a time. Theamount of opioid antagonist included in the dosage form may or may notcause a noticeable reduction in the level of analgesia elicited from,the dosage form upon oral administration, e.g., as measured bypharmacodynamic parameters such as a Visual Analogue Scale (“VAS”) fordrug effect, but preferably allows the dosage form to neverthelessprovide effective analgesia. In certain preferred embodiments of themethod, the dose of opioid antagonist appreciably affects a surrogatemeasure of opioid analgesic effect. In certain preferred embodiments,the amount of antagonist included in the oral dosage form is lesspositively reinforcing (e.g., less “liked”) by a non-physicallydependent subject than a comparable oral dosage form without theantagonist included.

The oral pharmaceutical compositions containing the inventivecombination of drags set forth herein may be in the form of tablets,liquids, troches, lozenges, aqueous or oily suspensions,multiparticulate formulations including dispersable powders, granules,matrix spheroids or coated inert beads, emulsions, hard or soft capsulesor syrups or elixirs, microparticles (e.g., microcapsules, microspheresand the like), buccal tablets, etc. The dosage forms of the presentinvention may include any desired pharmaceutically acceptable excipientsknown to those skilled in the art. The dosage forms May further providean immediate release of the opioid agonist and the opioid antagonist Incertain preferred embodiments, the dosage forms provide a sustainedrelease of the opioid agonist, and provide the part or all of the doseof opioid antagonist in (i) immediate release form, (ii) sustainedrelease form, or (iii) both immediate and sustained release form. Suchembodiments may further comprise a portion of the opioid agonist inimmediate release form. Sustained release may be accomplished inaccordance with formulations/methods of manufacture known to thoseskilled in the art of pharmaceutical formulation, e.g., via theincorporation of a sustained release carrier into a matrix containingthe opioid agonist and opioid antagonist; or via a sustained releasecoating of a matrix containing the opioid agonist and opioid antagonist.

The invention may provide for a safer product (e.g., less respiratorydepression) as well as one with a slower rate of opioid tolerance ‘andphysical dependency development.

In certain other preferred embodiments, the opioid included in thedosage form is a different orally active opioid agonist thanhydrocodone. The ratio of naltrexone included in such formulations canbe readily determined based on a simple calculation, taking into accountthe known equianalgesic dosages of various opioid analgesics as comparedto hydrocodone. Equianalgesic dosages of various opioid analgesics areprovided below, and are otherwise known to those skilled in the art,e.g., from Foley, K. “The Treatment of Cancer Pain;” N. Engl. J. Med.1985; 313:84-95, hereby incorporated by reference, In yet furtheraspects of this embodiment, a different opioid antagonist is substitutedfor naltrexone, using equiantagonistic doses thereof.

In certain embodiments, a combination of two opioid analgesics isincluded in the formulation. In further embodiments, one or more opioidanalgesics is included and a further non-opioid drug is also included,in addition to the opioid antagonist. Such non-opioid drugs wouldpreferably provide additional analgesia, and include, for example,aspirin, acetaminophen, non-steroidal antiinflammatory drugs (“NSAIDS”),NMDA antagonists, and cycooxygenase-II inhibitors (“COX-II inhibitors”),In yet further embodiments, a non-opioid drug can be included whichprovides a desired effect other than analgesia, e.g., antitussive,expectorant, decongestant, or antihistamine drugs, and the like.

The term “parenterally” as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection or infusiontechniques.

The term “effective analgesia” is defined for purposes of the presentinvention as a satisfactory reduction in or elimination of pain, alongwith a tolerable level of side effects, as determined by the humanpatient.

The term “sustained release” is defined for purposes of the presentinvention as the release of the drug (opioid analgesic) from the oralformulation at such a rate that blood (e.g., plasma) concentrations(levels) are maintained within the therapeutic range (above the minimumeffective analgesic concentration or “MEAC”) but below toxic levels overa period of time indicative of a twice-a-day or a once-a-dayformulation.

The term “steady state” refers to a time when the rate of elimination ofa drug is the same as the rate of absorption of that drug into the body.

For purposes of the present invention, the term “opioid agonist” isinterchangeable with the term “opioid” or “opioid analgesic” and shallinclude the base of the opioid, mixed agonist-antagonists, partialagonists, pharmaceutically acceptable salts thereof, stereoisomersthereof; ethers and esters thereof, and mixtures thereof.

For purposes of the present invention, the term “opioid antagonist”shall include the base, pharmaceutically acceptable salts thereof;stereoisomers thereof, ethers and esters thereof; and mixtures thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings are illustrative of embodiments of the inventionand are not meant to limit the scope of the invention as encompassed bythe claims.

FIG. 1 shows the naltrexone antagonism of hydrocodone-induced VAS(Visual Analog Scale) “drug effect” for Example 1;

FIG. 2 presents the naltrexone antagonism of hydrocodone-inducedpapillary constriction for Example 1;

FIG. 3 presents the mean “drug effect” VAS score over time for each ofthe treatments of Example 2;

FIG. 4 presents the mean “drug effect” pupil diameters over time foreach of the treatments of Example 2;

FIGS. 5 and 6 present the corresponding mean maximum “drug effect” VASscore (±95% CI) and mean minimum pupil diameter (±95% CI) versus the logfrom each of the naltrexone doses of Example 2;

FIG. 7A illustrates the subjects' ability to feel the effect ofhydrocodone in the presence of varying amounts of naltrexone in Example3;

FIGS. 7B and 7C illustrate the subjects' favorable or unfavorablesubjective experiences of hydrocodone in the presence of varying amountsof naltrexone, respectively, for Example 3;

FIG. 8A illustrates the subjects' perception of withdrawal from theeffect of hydrocodone in the presence of varying amounts of naltrexonein Example 3;

FIG. 8B illustrates the subjective experience of illness in the presenceof varying amounts of naltrexone in Example 3;

FIG. 9A illustrates the effect on pupil size of hydrocodone in thepresence of varying amounts of naltrexone in Example 3;

FIG. 9B illustrates the apparent extent of withdrawal from the effect ofhydrocodone in the presence of varying amounts of naltrexone in Example3, from the perspective of the observer;

FIGS. 10A-C present the areas under the curves presented in FIGS. 7A-C,integrated over the hour observation period, as a function of naltrexonedose, and the 95% confidence levels for the placebo response ofnaltrexone (30 mg hydrocodone 0 mg naltrexone); and

FIGS. 11A-C present the areas under the curves presented in FIG. 8A-Band FIG. 9A, integrated over the 6 hour observation period, as afunction of naltrexone dose, and the 95% confidence levels for theplacebo response of naltrexone (30 mg hydrocodone, 0 mg naltrexone).

DETAILED DESCRIPTION OF THE INVENTION

It has been postulated that there exists at least three subspecies ofopioid receptors, designated mu, kappa, and delta. Within thisframework, the mu receptor is considered to be involved in theproduction of superspinal analgesia, respiratory depression, euphoria,and physical dependence. The kappa receptor is considered to be involvedin inducing spinal analgesia, miosis and sedation. Activation of thegamma receptors causes dysphoria and hallucinations, as well asrespiratory and vasomotor stimulatory effects. A receptor distinct fromthe mu receptor and designated gamma has been described in the mouse vasdeferens, Lord, et al. Nature, 1977, 267, 495-99. Opioid agonists arethought to exert their agonist actions primarily at the mu receptor andto a lesser degree at the kappa receptor. There are a few drugs thatappear to act as partial agonists at one receptor type or another, Suchdrugs exhibit a ceiling effect. Such drugs include nalorphine, propiram,and buprenorphine. Still other drugs act as competitive antagonists atthe mu receptor and block the effects of morphine-like drugs, byexerting agonist actions at the kappa and omega receptors. The term“agonist-antagonist” has evolved to describe such mechanism, of actions.The concept of antagonism to the actions of opioids is considered to becomplex.

It has been found with the administration of opioid agonist-antagonistsand partial agonists that tolerance develops to the agonist effects butnot to the antagonist effects of the drugs. Even after prolongedadministration of high doses, discontinuance of naloxone is notcharacterized by any recognizable withdrawal syndrome, and withdrawal ofnaltrexone, another relatively pure opioid antagonist, produces very fewsigns and symptoms, However, after prolonged administration of highdosage, abrupt discontinuation of opioid agonist-antagonists nalorphineor cyclazocine causes a characteristic withdrawal syndrome that issimilar for both drugs.

Naloxone is an opioid antagonist which is almost void of agonisteffects. Subcutaneous doses of up to 12 mg of naloxone produce nodiscernable subjective effects, and 24 mg naloxone causes only slightdrowsiness. Small doses (0.4-0.8 mg) of naloxone given intramuscularlyor intravenously in man prevent or promptly reverse the effects ofmorphine-like opioid agonist. One mg of naloxone intravenously has beenreported to completely block the effect of 25 mg of heroin. The effectsof naloxone are seen almost immediately after intravenousadministration. The drug is absorbed after oral administration, but hasbeen reported to be metabolized into an inactive form rapidly in itsfirst passage through the liver such that it has been reported to beonly one fiftieth as potent as when parenterally administered. Oraldosage of more than 1 g have been reported to be almost completelymetabolized in less than 24 hours.

Other opioid antagonists, for example, cyclazocine and naltrexone, bothof which have cyclopropylmethyl substitutions on the nitrogen, retainmuch of their efficacy by the oral route and their durations of actionare much longer, approaching 24 hours after oral doses. A most preferredopioid antagonist is naltrexone. However, equiantagonistic oral doses ofother opioid antagonists, including but not limited to naloxone,nalmephene, cyclazocine, and levallorphan can be utilized in accordancewith the present invention. The ratio of such other antagonists to aparticular opioid agonist can be readily determined without undueexperimentation by one skilled in art who desires to utilize a differentopioid antagonist than naltrexone, the ratio of which to opioid agonistsis exemplified and discussed in detail herein. Those skilled in. the artmay determine such ratios of other antagonists to opioid agonists, e.g.,by conducting the same or similar clinical studies set forth in theexamples appended herein. Thus, combinations of opioidantagonists/opioid agonists which are orally administered in ratioswhich are equivalent to the ratio of, e.g., naltrexone to hydrocodoneset forth herein are considered to be within the scope of the presentinvention and within the scope of the; appended claims. For example, incertain embodiments of the invention, naloxone is utilized as the opioidantagonist, the amount of naloxone included in the dosage form beinglarge enough to provide an equiantagonistic effect as if naltrexone wereincluded in the combination.

In the treatment of patients previously addicted to opioid, naltrexonehas been used in large oral doses (over 100 mg) to prevent euphorigeniceffects of opioid agonists. Naltrexone has been reported to exert strongpreferential blocking action against mu over delta sites. Naltrexone isknown as a synthetic congener of oxymorphone with no opioid agonistproperties, and differs in structure from oxymorphone by the replacementof the methyl group located on the nitrogen atom of oxymorphone with acyclopropylmethyl group, The hydrochloride salt of naltrexone is solublein water up to about 100 mg/cc. The pharmacological and pharmacokineticproperties of naltrexone have been evaluated in multiple animal andclinical studies. See, e.g., Gonzalez J P, et al. Naltrexone: A reviewof its Pharmacodynamic and Pharmacokinetic Properties and TherapeuticEfficacy in the Management of Opioid Dependence. Drugs 1988; 35:192-213,hereby incorporated by reference. Following oral administration,naltrexone is rapidly absorbed (within 1 hour) and has an oralbioavailability ranging from 5-40%. Naltrexone's protein binding isapproximately 21% and the volume of distribution following single-doseadministration is 16.1 L/kg.

Naltrexone is commercially available in tablet form (Revia®, DuPont) forthe treatment of alcohol dependence and for the blockade of exogenouslyadministered opioids. See, e.g., Revia (naltrexone hydrochloridetablets). Physician's Desk Reference 51^(st) ed., Montvale, N.J.“Medical Economics” 1997; 51:957-959. A dosage of 50 mg ReVia® blocksthe pharmacological effects of 25 mg IV administered heroin for up to 24hours.

It is known that when coadministered with morphine, heroin or otheropioids on a chronic basis, naltrexone blocks the development ofphysical dependence to opioids. It is believed that the method by whichnaltrexone blocks the effects of heroin is by competitively binding atthe opioid receptors. Naltrexone has been used to treat narcoticaddiction by complete blockade of the effects of opioids. It has beenfound that the most successful use of naltrexone for a narcoticaddiction is with good prognosis narcotic addicts as part of acomprehensive occupational or rehabilitative program involvingbehavioral control or other compliance enhancing methods. For treatmentof narcotic dependence with naltrexone, it is desirable that the patientbe opioid-free for at least 7-10 days. The initial dosage of naltrexonefor such purposes has typically been about 25 mg, and if no withdrawalsigns occur, the dosage may be increased to 50 mg per day. A dailydosage of 50 mg is considered to produce adequate clinical blockade ofthe actions of parenterally administered opioids. Naltrexone has alsobeen used for the treatment of alcoholism as an adjunct with social andpsychotherapeutic methods.

In the dosage forms and methods of the invention, the amount ofnaltrexone included is significantly less than the dosages previouslycommercially available. This is in part because the use of naltrexone isdifferent in the present invention: the goal is not to block opioideffects, but rather to provide a negative, “aversive” experience when alarge amount of the combination product, e.g., about 2-3 limes theusually prescribed dose, is taken by or administered to a physicallydependent subject.

Thus, for example, in formulations, of the present invention in whichthe opioid is hydrocodone bitartrate 15 mg, the amount of naltrexonehydrochloride included in the formulation is from about 0.5 mg to about4 mg, and preferably from about 0.75 mg to about 3 mg naltrexone per 15mg hydrocodone.

Opioid analgesics which are useful in the present invention include allopioid agonists or mixed agonist-antagonists, partial agonists,including but not limited to alfentanil, allylprodine, alphaprodine,anileridine, benzylmorphine, bezitramnide, buprenorphine, butorphanol,clonitazene, codeine, desomorphine, dextromoramide, dezocine,diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaheptyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, fentanyl, heroin, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levorphanol,levophenacylmorphan, lofentanil, mereperidine, meptazinol, metazocine,methadone, metopone, morphine, myrophine, narceine, nicomorphine,norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine,norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, propheptazine, promedol, properidine, pro-poxyphene,sufentanil, tilidine, tramadol, mixtures of any of the foregoing, saltsof any of the foregoing, and the like.

In certain preferred embodiments, the opioid agonist or analgesic isselected from the group consisting of hydrocodone, morphine,hydromorphone, oxycodone, codeine, levorphanol, meperidine, methadone,or salts thereof, or mixtures thereof. In certain preferred embodiments,the opioid agonist is hydrocodone. Equianalgesic doses of these opioids,in comparison to a 15 mg dose of hydrocodone, are set forth in Table 1below:

TABLE 1 Equianalgesic Doses of Opioids Opioid Calculated Dose (mg)Oxycodone 13.5 Codeine 90.0 Hydrocodone 15.0 Hydromorphone 3.375Levorphanol 1.8 Meperidine 135.0 Methadone 9.0 Morphine 27.0

Based on the preferred ratio of naltrexone in an amount from about 0.5to about 4 mg per 15 mg of hydrocodone, the approximate ratio ofnaltrexone to 1 mg of each opioid is set forth in Table 2:

TABLE 2 Weight Ratio of Naltrexone per Dose Opioid Weight RatioNaltrexone Opioid per 1 mg Opioid Oxycodone 0.037 to 0.296 Codeine 0.005to 0.044 Hydrocodone 0.033 to 0.267 Hydromorphone 0.148 to 1.185Levorphanol 0.278 to 2.222 Meperidine 0.0037 to 0.0296 Methadone 0.056to 0.444 Morphine 0.018 to 0.148

Based on the more preferred ratio of about 0.75 mg to about 3 mgnaltrexone per 15 mg hydrocodone of naltrexone, the approximate ratio ofnaltrexone to ling of each opioid is set forth in Table 3:

TABLE 3 Weight Ratio of Naltrexone per Dose Opioid Opioid Weight RatioNaltrexone Oxycodone 0.056 to 0.222 Codeine 0.0083 to 0.033  Hydrocodone0.050 to 0.200 Hydromorphone 0.222 to 0.889 Levorphanol 0.417 to 1.667Meperidine 0.0056 to 0.022  Methadone 0.083 to 0.333 Morphine 0.028 to0.111

Although hydrocodone is effective in the management of pain, there hasbeen an increase in its abuse by individuals who are psychologicallydependent on opioids or who misuse opioids for non-therapeutic reasons.Previous experience with other opioids has demonstrated a decreasedabuse potential when opioids are administered in combination with anarcotic antagonist especially in patients who are ex-addicts. WeinholdL L, et al. Buprenorphine Alone and in Combination with Naltrexone inNon-Dependent Humans, Drug and Alcohol Dependence 1992; 30:263-274;Mendelson J., et. al., Buprenorphine and Naloxone Interactions inOpiate-Dependent Volunteers, Clin Pharme Ther 1996; 60:105-114; both ofwhich are hereby incorporated by reference.

Hydrocodone is a semisynthetic narcotic analgesic and antitussive withmultiple central nervous system and gastrointestinal actions.Chemically, hydrocodone is 4,5-epoxy-3-methoxy-17-methylmorphinan-6-one,and is also known as dihydrocodeinone. Like other opioids, hydrocodonemay be habit forming and may produce drug dependence of the morphinetype. In excess doses hydrocodone, like other opium derivatives, willdepress respiration.

Oral hydrocodone is also available in Europe (Belgium, Germany, Greece,Italy, Luxembourg, Norway and Switzerland) as an antitussive agent. Aparenteral formulation is also available in Germany as an antitussiveagent. For use as an analgesic, hydrocodone bitartrate is commerciallyavailable in the United States only as a fixed combination withnon-opiate drugs (i.e., ibuprofen, acetaminophen, aspirin, etc.) forrelief of moderate or moderately severe pain.

A common dosage form of hydrocodone is in combination withacetaminophen, and is commercially available, e.g., as Lortab® in theU.S. from UCB Pharma, Inc. as 2.5/500 mg, 5/500 mg, 7.5/500 mg and10/500 mg hydrocodone/acetaminophen tablets. Tablets are also availablein the ratio of 7.5 mg hydrocodone bitartrate and 650 mg acetaminophen;and 7.5 mg hydrocodone bitartrate and 750 m.g acetaminophen. Hydrocodonein combination with aspirin is given in an oral dosage form to adultsgenerally in 1-2 tablets every 4-6 hours as needed to alleviate pain.The tablet form is 5 mg hydrocodone bitartrate and 224 mg aspirin with32 mg caffeine; or 5 mg hydrocodone bitartrate and 500 mg aspirin. Arelatively new formulation comprises hydrocodone bitartrate andibuprofen. Vicoprofen®, commercially available in the U.S. from KnollLaboratories, is a tablet containing 7.5 mg hydrocodone bitartrate and200 mg ibuprofen. The present invention is contemplated to encompass allsuch formulations, with the inclusion of the orally active opioidantagonist within the inventive amounts set forth herein,

The abuse potential of opioid analgesics such as hydrocodone issurprisingly curtailed by the inventive combinations or the presentinvention. More particularly, it has been discovered that it is possibleto combine in a single oral dosage form an opioid analgesic togetherwith a small amount of opioid antagonist, to achieve a product whichstill provides analgesia but which substantially negates the possibilitythat a physically dependent human subject will continue to abuse thedrug by taking more than one tablet at a time, e.g., 2-3 times more thanthe usually prescribed dose.

The oral dosage forms of the invention comprise an orallytherapeutically effective amount of an opioid agonist, together with anopioid antagonist such as naltrexone in an amount (i) which does notcause a reduction in the level of analgesia elicited from the dosageform upon oral administration to a non-therapeutic level and (ii) whichprovides at least a mildly negative, “aversive” experience in physicallydependent human subjects, for example, physically dependent addicts(e.g., precipitated abstinence syndrome) when taking more than theusually prescribed dose at a time. Preferably, the amount of antagonistincluded in the oral dosage form is (iii) less positively reinforcing(e.g., less “liked”) by a non-physically dependent human subject, e.g.,opioid addict, than a comparable oral dosage form without the antagonistincluded.

The amount of antagonist which is useful to achieve parameters (i)-(iii)set forth in the preceding paragraph may be determined at least in part,for example, through the use of “surrogate” tests, such as a VAS scale(where the subject grades his/her perception of the effect of the dosageform) and/or via a. measurement such as pupil size (measured bypupillometry). Such measurements allow one skilled in the art todetermine the dose of antagonist relative to the dose of agonist whichcauses a diminution in the opiate effects of the agonist. Subsequently,one skilled in the art can determine the level of opioid antagonist thatcauses aversive effects in physically dependent subjects as well as thelevel of opioid antagonist that minimizes “liking scores” or opioidreinforcing properties in non-physically dependent addicts. Once theselevels of opioid antagonist are determined, it is then possible todetermine the range of antagonist dosages at or below this level whichwould be useful in achieving parameters (i) (iii) set forth in thepreceding paragraph.

The combination of opioid agonist and opioid antagonist can be employedin admixtures with conventional excipients, i.e., pharmaceuticallyacceptable organic or inorganic carrier substances suitable for oraladministration, known to the art. Suitable pharmaceutically acceptablecarriers include but are not limited to water, salt solutions, alcohols,gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols,gelate, carbohydrates such as lactose, amylose or starch, magnesiumstearate talc, silicic acid, viscous paraffin, perfume oil, fatty acidmonoglycerides and diglycerides, pentaerythritol fatty acid esters,hydroxymethylcellulose, polyvinylpyrrolidone, etc. The pharmaceuticalpreparations can be sterilized and if desired mixed with auxiliaryagents, e.g., lubricants, preservatives, stabilizers, wetting agents,emulsifiers, salts for influencing osmotic pressure buffers, coloring,flavoring and/or aromatic substances and the like. They can also becombined where desired with other active agents, e.g., other analgesicagents. For oral administration, particularly suitable are tablets,dragees, liquids, drops, suppositories, or capsules, caplets andgelcaps. The compositions intended for oral use may be preparedaccording to any method known in the art and such compositions maycontain one or more agents selected from the group consisting of inert,non-toxic pharmaceutically excipients which are suitable for themanufacture of tablets. Such excipients include, for example an inertdiluent such as lactose; granulating and disintegrating agents such ascornstarch; binding agents such as starch; and lubricating agents suchas magnesium stearate. The tablets may be uncoated or they may be coatedby known techniques for elegance or to delay release of the activeingredients. Formulations for oral use may also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertdiluent.

Aqueous suspensions contain the above-identified combination of drugsand that mixture has one or more excipients suitable as suspendingagents, for example pharmaceutically acceptable synthetic gums such ashydroxypropylmethylcellulose or natural gums. Oily suspensions may beformulated by suspending the above-identified combination of drugs in avegetable oil or mineral oil. The oily suspensions may contain athickening agent such as beeswax or cetyl alcohol. A syrup, elixir, orthe like can be used wherein a sweetened vehicle is employed. Injectablesuspensions may also be prepared, in which case appropriate liquidcarriers, suspending agents and the like may be employed.

The method of treatment and pharmaceutical formulations of the presentinvention may further include One or more drugs in addition to theopioid analgesic and opioid antagonist, which additional drugs) may ormay not act synergistically therewith, Thus, in certain embodiments, acombination of two opioid analgesics may be included in the formulation,in addition to the opioid antagonist. For example, the dosage form mayinclude two opioid analgesics having different properties, such ashalf-life, solubility, potency, and a combination of any of theforegoing. In yet further embodiments, one or more opioid analgesics isincluded and a further non-opioid drug is also included, in addition tothe opioid antagonist, Such non-opioid drugs would preferably provideadditional analgesia, and include, for example, aspirin; acetaminophen;non-sterioidal antiinflammatory drugs (“NSAMS”), e.g., ibuprofen,ketoprofen, etc.; N-methyl-D-aspartate (NNIDA) receptor antagonists,e.g., a morphinan such as dextromethorphan or dextrorphan, or ketamine;cycooxygenase-II inhibitors (“COX-II inhibitors”); anchor glycinereceptor antagonists.

In certain preferred embodiments of the present invention, the inventionallows for the use of lower doses of the opioid analgesic by virtue ofthe inclusion of an additional non-opioid agonist, such as an NSAID or aCOX-2 inhibitor. By using lower amounts of either or both drugs, theside effects associated with effective pain management in humans arereduced.

Suitable non-steroidal anti-inflammatory agents, including ibuprofen,diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen,ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen,muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid,fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac,tiopinac, zido-metacin, acemetacin, fentiazac, clidanac, oxpinac,mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid,tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam orisoxicam, and the like. Useful dosages of these drugs are well known tothose skilled in the art.

N-methyl-D-aspartate (NMDA) receptor antagonists are well known in theart, and encompass, for example, morphinans such as dextromethorphan ordextrorphan, ketamine, d-methadone or pharmaceutically acceptable saltsthereof. For purposes of the present invention, the term “NMDAantagonist” is also deemed to encompass drugs that block a majorintracellular consequence of NMDA-receptor activation, e.g. aganglioside such as GM_(I) or GM_(Ib) a phenothiazine such astrifluoperazine or a naphthalenesulfonamide such asN-(6-aminothexyl)-5-chloro-1-naphthalenesulfonamide. These drugs arestated to inhibit the development of tolerance to and/or dependence onaddictive drugs, e.g., narcotic analgesics such as morphine, codeine,etc. in U.S. Pat. Nos. 5,321,012 and 5,556,838 (both to Mayer, et al.),and to treat chronic pain in U.S. Pat. No. 5,502,058 (Mayer, et al.),all of which are hereby incorporated by reference. The NMDA antagonistmay be included alone, or in combination with a local anesthetic such aslidocaine, as described in these Mayer, et al. patents.

The treatment of chronic pain via the use of glycine receptorantagonists and the identification of such drugs is described in U.S.Pat. No. 5,514,480 (Weber, et al.), hereby incorporated by reference.

COX-2 inhibitors have been reported in the art and many chemicalstructures are known to produce inhibition of cyclooxygenase-2. COX-2inhibitors are described, for example, in U.S. Pat. Nos. 5,616,601;5,604,260; 5,593,994; 5,550,142; 5,536,752; 5,521,213; 5,475,995;5,639,780; 5,604,253; 5,552,422; 5,510,368; 5,436,265; 5,409,944; and5,130,311, all of which are hereby incorporated by reference. Certainpreferred COX-2 inhibitors include celecoxib (SC-58635), DUP-697,flosulide (CGP-28238), meloxicam, 6-methoxy-2 naphthylacetic acid(6-MNA), MK-966, nabtunetone (prodrug for 6-MNA), nimesulide, NS-398,SC-5766, SC-58215, T-614; or combinations thereof. Dosage levels ofCOX-2 inhibitor on the order of from about 0.005 mg to about 140 mg perkilogram of body weight per day are therapeutically effective incombination with an opioid analgesic. Alternatively, about 0.25 mg toabout 7 g per patient per day of a COX-2 inhibitor is administered incombination with an opioid analgesic.

In yet further embodiments, a non-opioid drug can be included whichprovides a desired effect other than analgesia, e.g., antitussive,expectorant, decongestant, antihistamine drugs, local anesthetics, andthe like,

An oral dosage form according to the invention may be provided as, forexample, granules, spheroids, beads, pellets (hereinafter collectivelyreferred to as “multiparticulates”) An amount of the multiparticulateswhich is effective to provide the desired dose of opioid over time maybe placed in a capsule or may be incorporated in any other suitable oralsolid form. Alternatively, the oral dosage form may be in the form of atablet.

Controlled Release Dosage Forms

The opioid agonist/opioid antagonist combination can be formulated as acontrolled or sustained release oral formulation in any suitable tablet,coated tablet or multiparticulate formulation known to those skilled inthe art. The sustained release dosage form may optionally include asustained release carrier which is incorporated into a matrix along withthe opioid agonist and opioid antagonist, or may be applied as asustained release coating.

In embodiments in which the opioid analgesic comprises hydrocodone, thesustained release oral dosage forms may include analgesic doses fromabout 8 mg to about 50 mg of hydrocodone per dosage unit. In sustainedrelease oral dosage forms where hydromorphone is the therapeuticallyactive opioid, it is included in an. amount from about 2 mg to about 64mg hydromorphone hydrochloride. In another embodiment, the opioidanalgesic comprises morphine, and the sustained release oral dosageforms of the present invention include from about 2.5 mg to about 800 mgmorphine, by weight. In yet another embodiment, the opioid analgesiccomprises oxycodone and the sustained release oral dosage forms includefrom about 2.5 mg to about 800 mg oxycodone. The opioid analgesic maycomprise tramadol and the sustained release oral dosage forms mayinclude from about 25 mg to 800 mg tramadol per dosage unit. The dosageform may contain more than one opioid analgesic to provide asubstantially equivalent therapeutic effect. Alternatively, the dosageform may contain molar equivalent amounts of other salts of the opioidsuseful in the present invention.

In one preferred embodiment of the present invention, the sustainedrelease dosage form comprises such particles containing or comprisingthe active ingredient, wherein the particles have diameter from about0.1 mm to about 2.5 mm, preferably from about 0.5 mm to about 2 mm.

The particles are preferably film coated with a material that permitsrelease of the opioid agonist/antagonist combination at a sustained ratein an aqueous medium. The film coat is chosen so as to achieve, incombination with the other stated properties, a desired in-vitro releaserate. The sustained release coating formulations of the presentinvention should be capable of producing a strong, continuous film thatis smooth and elegant, capable of supporting pigments and other coatingadditives, non-toxic, inert, and tack-free.

In certain embodiments, the particles comprise normal release matrixescontaining the opioid analgesic with the opioid antagonist.

Coatings

The dosage forms of the present invention may optionally be coated withone or more materials suitable for the regulation of release or for theprotection of the formulation. In one embodiment, coatings are providedto permit either pH-dependent or pH-independent release, e.g., whenexposed to gastrointestinal fluid. A pH-dependent coating serves torelease the opioid in desired areas of the gastro-intestinal (GI) tract,e.g., the stomach or small intestine, such that an absorption profile isprovided which is capable of providing at least about eight hours andpreferably about twelve hours to up to about twenty-four hours ofanalgesia to a patient. When a pH-independent coating is desired, thecoating is designed to achieve optimal release regardless of pH-changesin the environmental fluid, e.g., the GI tract. It is also possible toformulate compositions which release a portion of the dose in onedesired area of the GI tract, e.g., the stomach, and release theremainder of the dose in another area of the GI tract, e.g., the smallintestine.

Formulations according to the invention that utilize pH-dependentcoatings to obtain formulations may also impart a repeat-action effectwhereby unprotected drug is coated over the enteric coat and is releasedin the stomach, while the remainder, being protected by the entericcoating, is released further down the gastrointestinal tract coatingswhich are pH-dependent may be used in accordance with the presentinvention include shellac, cellulose acetate phthalate (CAP), polyvinylacetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate, andmethacrylic acid ester copolymers, zein, and the like.

In certain preferred embodiments, the substrate (e.g., tablet core bead,matrix particle) containing the opioid analgesic (with or without theCOX-2 inhibitor) is coated with a hydrophobic material selected from (i)an alkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof.The coating may be applied in the form of an organic or aqueous solutionor dispersion. The coating may be applied to obtain a weight gain fromabout 2 to about 25% of the substrate in order to obtain a desiredsustained release profile. Coatings derived from aqueous dispersions—aredescribed, e.g., in detail in U.S. Pat. Nos. 5,273,760 and 5,286,493,assigned to the Assignee of the present invention and herebyincorporated by reference.

Other examples of sustained release formulations and coatings which maybe used in accordance with the present invention include Assignee's U.S.Pat. Nos. 5,324,351; 5,356,467, and 5,472,712, hereby incorporated byreference in their entirety.

Alkylcellulose Polymers

Cellulosic materials and polymers, including alkylcelluloses, providehydrophobic materials well suited for coating the beads according to theinvention, Simply by way of example, one preferred alkylcellulosicpolymer is ethylcellulose, although the artisan will appreciate thatother cellulose and/or akylcellulose polymers may be readily employed,singly or in any combination, as all or part of a hydrophobic coatingaccording to the invention.

One commercially-available aqueous dispersion of ethylcellulose isAquacoat® (FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat® is preparedby dissolving the ethylcellulose in a water immiscible organic solventand then emulsifying the same in water in the presence of a surfactantand a stabilizer. After homogenization to generate submicron droplets,the organic solvent is evaporated under vacuum to form a pseudolatex.The plasticizer is not incorporated in the pseudolatex during themanufacturing phase. Thus, prior to using the same as a coating, it isnecessary to intimately mix the Aquacoat® with a suitable plasticizerprior to use.

Another aqueous dispersion of ethylcellulose is commercially availableas Surelease® (Colorcen, Inc., West Point, Pa., U.S.A.). This product isprepared by incorporating plasticizer into the dispersion during themanufacturing process. A hot melt of a polymer, plasticizer (dibutylsebacate), and stabilizer (oleic acid) is prepared as a homogeneousmixture, which is then diluted with an alkaline solution to obtain anaqueous dispersion which can be applied directly onto substrates.

Acrylic Polymers

In other preferred embodiments of the present invention, the hydrophobicmaterial comprising the controlled release coating is a pharmaceuticallyacceptable acrylic polymer, including but not limited to acrylic acidand methacrylic acid copolymers, methyl methacrylate copolymers,ethoxyethyl methacrylates; cyanoethyl methacrylate, poly(methacrylicacid), poly(methacrylic acid), methacrylic acid alkylamide copolymer,poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate)copolymer, polyacrylamide, aminoalkyl methacrylate copolymer,poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers,

In certain preferred embodiments, the acrylic polymer is comprised ofone or more ammonio methacrylate copolymers Ammonia methacrylatecopolymers are well known in the art, and are described in NF XVII asfully polymerized copolymers of acrylic and methacrylic acid esters witha low content of quaternary ammonium groups.

In order to obtain a desirable dissolution profile, it may be necessaryto incorporate two or more ammonio methacrylate copolymers havingdiffering physical properties, such as different molar ratios of thequaternary ammonium groups to the neutral (meth)acrylic esters.

Certain methacrylic acid ester-type polymers are useful for preparingpH-dependent coatings which may be used in accordance with the presentinvention. For example, there are a family of copolymers synthesizedfrom diethylaminoethyl methacrylate and other neutral methacrylicesters, also known as methacrylic acid copolymer or polymericmethacrylates, commercially available as Eudragit® from Röhm Tech, Inc.There are several different types of Eudragit®. For example, Eudragit® Eis an example of a methacrylic acid copolymer which swells and dissolvesin acidic media. Eudragit® L is a methacrylic acid copolymer which doesnot swell at about pH<5.7 and is soluble at about pH>6. Eudragit® S doesnot swell at about pH<6.5 and is soluble at about pH>7. Eudragit® RL andEudragit® RS are water swellable, and the amount of water absorbed bythese polymers is pH-dependent, however, dosage forms coated withEudragit® RT, and RS are pH-independent.

In certain preferred embodiments, the acrylic coating comprises amixture of two acrylic resin lacquers commercially available from RöhmPharma under the Tradenames Eudragit®RL30D and Eudragit® RS30D,respectively. Eudragit® RL30D and Eudragit® RS30D are copolymers ofacrylic and methacrylic esters with a low content of quaternary ammoniumgroups, the molar ratio of ammonium groups to the remaining neutral(meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit®RS30D. The mean molecular weight is about 150,000. The code designationsRL (high permeability) and RS (low permeability) refer to thepermeability properties of these agents. Eudragit® RL/RS mixtures areinsoluble in water and in digestive fluids. However, coatings formedfrom the same are swellable and permeable in aqueous solutions anddigestive fluids.

The Eudragit® RL/RS dispersions of the present invention may be mixedtogether in any desired ratio in order to ultimately obtain a sustainedrelease formulation having a desirable dia. solution profile. Desirablesustained release formulations may be obtained, for instance, from aretardant coating derived from 100% Eudragit® RL, 50% Eudragit® RL and50% Eudragit® RS, and 10% Eudragit® RL:Eudragit® 90% RS. Of course, oneskilled in the art will recognize that other acrylic polymers may alsobe used, such as, for example, Eudragit® L.

Plasticizers

In embodiments of the present invention where the coating comprises anaqueous dispersion of a hydrophobic material, the inclusion of aneffective amount of a plasticizer in the aqueous dispersion ofhydrophobic material will further improve the physical properties of thesustained release coating. For example, because ethylcellulose has arelatively high glass transition temperature and does not form flexiblefilms under normal coating conditions, it is preferable to incorporate aplasticizer into au ethylcellulose coating containing sustained releasecoating before using the same as a coating material. Generally, theamount of plasticizer included in a coating solution is based on theconcentration of the film-former, e.g., most often from about 1 to about50 percent by weight of the film-former. Concentration of theplasticizer, however, can only be properly determined after carefulexperimentation with the particular coating solution and method ofapplication.

Examples of suitable plasticizers for ethylcellulose include waterinsoluble plasticizers such as dibutyl sebacate, diethyl phthalate,triethyl citrate, tributyl citrate, and triacetin, although it ispossible that other water-insoluble plasticizers (such as acetylatedmonoglycerides, phthalate esters, castor oil, etc.) may be used.Triethyl citrate is an especially preferred plasticizer for the aqueousdispersions of ethyl cellulose of the present invention.

Examples of suitable plasticizers for the acrylic polymers of thepresent invention include, but are not limited to citric acid esterssuch as triethyl citrate NF XVI, tributyl citrate dibutyl phthalate, andpossibly 1,2-propylene glycol. Other plasticizers which have proved tobe suitable for enhancing the elasticity of the films formed fromacrylic films such as Eudragit® RL/RS lacquer solutions includepolyethylene glycols, propylene glycol, diethyl phthalate, castor oil,and triacetin. Triethyl citrate is an especially preferred plasticizerfor the aqueous dispersions of ethyl cellulose of the present invention.

It has further been found that the addition of a small amount of talcreduces the tendency of the aqueous dispersion to stick duringprocessing, and acts as a polishing agent.

Processes for Preparing Coated Beads

When a hydrophobic material is used to coat inert pharmaceutical beadssuch as nu pariel 18/20 beads, a plurality of the resultant solidcontrolled release beads may thereafter be placed in a gelatin capsulein an amount sufficient to provide an effective controlled release dosewhen ingested and contacted by an environmental fluid, e.g., gastricfluid or dissolution media.

The controlled release bead formulations of the present invention slowlyrelease the therapeutically active agent, e.g., when ingested andexposed to gastric fluids, and then to intestinal fluids. The controlledrelease profile of the formulations of the invention can be altered, forexample, by varying the amount of overcoating with the hydrophobicmaterial, altering the manner in which the plasticizer is added to thehydrophobic material, by varying the amount of plasticizer relative tohydrophobic material, by the inclusion of additional ingredients orexcipients, by altering the method of manufacture, etc, The dissolutionprofile of the ultimate product may also be modified, for example, byincreasing or decreasing the thickness of the retardant coating.

Spheroids or beards coated with a therapeutically active agent areprepared, e.g., by dissolving the therapeutically active agent in waterand then spraying the solution onto a substrate, for example, nu pariel18/20 beads, using a Wuster insert. Optionally, additional ingredientsare also added prior to coating the beads in order to assist the bindingof the opioid to the beads, and/or to color the solution, etc. Forexample, a product which includes hydroxypropylmethylcellulose, etc.with or without colorant (e.g., Opadry®, commercially available fromColorcon, Inc.) may be added to the solution and the solution mixed(e.g., for about I hour) prior to application of the same onto thebeads. The resultant coated substrate, in this example beads, may thenbe optionally overcoated with a barrier agent, to separate thetherapeutically active agent from the hydrophobic controlled releasecoating. An example of a suitable barrier agent is one which compriseshydroxypropylmethylcellulose. However, any film-former known in the artmay be used. It is preferred that the hairier agent does not affect thedissolution rate of the final product.

The beads may then be overcoated with an aqueous dispersion of thehydrophobic material. The aqueous dispersion of hydrophobic materialpreferably further includes an effective amount of plasticizer, e.g. triethyl citrate. Pre-formulated aqueous dispersions of ethyl-cellulose,such as Aquacoat® or Surelease®, may be used. If Surelease® is used, itis not necessary to separately add a plasticizer. Alternatively,pre-formulated aqueous dispersions of acrylic polymers such as Eudragit®can be used.

The coating solutions of the present invention preferably contain, inaddition to the film-former, plasticizer, and solvent system (i.e.,water), a colorant to provide elegance and product ‘distinction, Colormay be added to the solution of the therapeutically active agentinstead, or in addition to the aqueous dispersion of hydrophobicmaterial. For example, color may be added to Aquacoat® via the use ofalcohol or propylene glycol based color dispersions, milled aluminumlakes and opacifiers such as titanium dioxide by adding color with shearto water soluble polymer solution and then using low shear to theplasticized Aquacoat®. Alternatively, any suitable method of providingcolor to the formulations of the present invention may be used. Suitableingredients for providing color to the formulation when an aqueousdispersion of an acrylic polymer is used include titanium dioxide andcolor pigments, such as iron oxide pigments. The incorporation ofpigments, may, however, increase the retard effect of the coating.

Plasticized hydrophobic material may be applied onto the substratecomprising the therapeutically active agent by spraying using anysuitable spray equipment known in the art. In a preferred method, aWurster fluidized-bed system is used in which an air jet, injected fromunderneath, fluidizes the core material and effects drying while theacrylic polymer coating is sprayed on. A sufficient amount of thehydrophobic material to obtain a predetermined controlled release ofsaid therapeutically active agent when the coated substrate is exposedto aqueous solutions, e.g., gastric fluid, is preferably applied, takinginto account the physical characteristics of the therapeutically activeagent, the manner of incorporation of the plasticizer, etc. Aftercoating with the hydrophobic material, a further overcoat of afilm-former, such as Opadry®, is optionally applied to the beads. Thisovercoat is provided, if at all, in order to substantially reduceagglomeration of the beads.

The release of the therapeutically active agent from the controlledrelease formulation of the present invention can be further influenced,i.e., adjusted to a desired rate, by the addition of one or morerelease-modifying agents, or by providing one or more passagewaysthrough the coating. The ratio of hydrophobic material to water solublematerial is determined by, among other factors, the release raterequired and the solubility characteristics of the materials selected.

The release-modifying agents which function as pore-formers may beorganic or inorganic, and include materials that can be dissolved,extracted or leached from the coating in the environment of use. Thepore-formers may comprise one or more hydrophilic materials such ashydroxypropylmethylcellulose.

The sustained release coatings of the present invention can also includeerosion-promoting agents such as starch and gums.

The sustained release coatings of the present invention can also includematerials useful for making microporous lamina in the environment ofuse, such as polycarbonates comprised of linear polyesters of carbonicacid in which carbonate groups reoccur in the polymer chain,

The release-modifying agent may also comprise a semi-permeable polymer.

In certain preferred embodiments, the release-modifying agent isselected from hydroxypropylmethylcellulose, lactose, metal stearates,and mixtures of any of the foregoing.

The sustained release coatings of the present invention may also includean exit means comprising at least one passageway, orifice, or the like.The passageway may be formed by such methods as those disclosed in U.S.Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864 (all of whichare hereby incorporated by reference). The passageway can have any shapesuch as round, triangular, square, elliptical, irregular, etc.

Matrix Bead Formulations

In other embodiments of the present invention, the controlled releaseformulation is achieved via a matrix having a controlled release coatingas set forth above. The present invention may also utilize a controlledrelease matrix that affords in dissolution rates of the opioid withinthe preferred ranges and that releases the opioid in a pH-dependent orpH-independent manner. The materials suitable for inclusion in acontrolled release matrix will depend on the method used to form thematrix.

For example, a matrix in addition to the opioid analgesic and(optionally) COX-2 may include:

Hydrophilic and/or hydrophobic materials, such as gums, celluloseethers, acrylic resins, protein derived materials; the list is not meantto be exclusive, and any pharmaceutically acceptable hydrophobicmaterial or hydrophilic material which: is capable of impartingcontrolled release of the active agent and which melts (or softens tothe extent necessary to be extruded) may be used in accordance with thepresent invention.

Digestible, long chain (C₈-C₅₀, especially C₁₂-C₄₀), substituted orunsubstituted hydrocarbons, such as fatty acids, fatty alcohols,glyceryl esters of fatty acids, mineral and vegetable oils and waxes,and stearyl alcohol; and polyalkylene glycols.

Of these polymers, acrylic polymers, especially Eudragit® RSPO—thecellulose ethers, especially hydroxyalkylcelluloses andcarboxyalkylcelluloses, are preferred. The oral dosage form may containbetween 1% and 80% (by weight) of at least one hydrophilic orhydrophobic material,

When the hydrophobic material is a hydrocarbon, the hydrocarbonpreferably has a melting point of between 25° and 90° a of the longchain hydrocarbon materials, fatty (aliphatic) alcohols are preferred.The oral dosage form may contain up to 60% (by weight) of at least onedigestible, long chain hydrocarbon.

Preferably, the oral dosage form contains up to 60% (by weight) of atleast one polyalkylene glycol.

The hydrophobic material is preferably selected from the groupconsisting of alkylcelluloses, acrylic and methacrylic acid polymers andcopolymers, shellac, zein, hydrogenated castor oil, hydrogenatedvegetable oil, or mixtures thereof in certain preferred embodiments ofthe present invention, the hydrophobic material is a pharmaceuticallyacceptable acrylic polymer, including but not limited to acrylic acidand methacrylic acid copolymers, methyl methacrylate, methylmethacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamine copolymer,poly(methyl methacrylate), poly(methacrylic acid)(anhydride),polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers. In other embodiments, the hydrophobicmaterial is selected from materials such as hydroxyalkylcelluloses suchas hydroxypropylmethylcellulose and mixtures of the foregoing.

Preferred hydrophobic materials are grater-insoluble with more or lesspronounced hydrophilic and/or hydrophobic trends. Preferably, thehydrophobic materials useful in the invention have a melting point fromabout 30° to about 200° C., preferably from about 45° to about 90° C.Specifically, the hydrophobic material may comprise natural or syntheticwaxes, fatty alcohols (such as lauryl, myristyl, stearyl, oetyl orpreferably cetostearyl alcohol), fatty acids, including but not limitedto fatty acid esters, fatty acid glycerides (mono-, di-, andtri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearicaid, stearyl alcohol and hydrophobic and hydrophilic materials havinghydrocarbon backbones: Suitable waxes include, for example, beeswax,glycowax, castor wax and carnauba wax. For purposes of the presentinvention, a wax-like substance is defined as any material which isnormally solid at room temperature and has a melting point of from about30° to about 100° C.

Suitable hydrophobic materials which may be used in accordance with thepresent invention include digestible, long chain (C₈-C₅₀, especiallyC₁₂-C₄₀), substituted or unsubstituted hydrocarbons, such as fattyacids, fatty alcohols, glyceryl esters of fatty acids, mineral andvegetable oils and natural and synthetic waxes, Hydrocarbons having amelting point of between 25° and 90° C. are preferred. Of the long chainhydrocarbon materials, fatty (aliphatic) alcohols are preferred incertain embodiments. The oral dosage form may contain up to 60% (byweight) of at least one digestible, long chain hydrocarbon.

Preferably, a combination of two or more hydrophobic materials areincluded in the matrix formulations. If an additional hydrophobicmaterial is included, it is preferably selected from natural andsynthetic waxes, fatty acids, fatty alcohols, and mixtures of the same.Examples include beeswax, carnauba wax, stearic acid and stearylalcohol. This list is meant to be exclusive.

One particular suitable matrix comprises at least one water solublehydroxyalkyl cellulose, at least one C₁₂-C₃₆, preferably C₁₄-C₂₂,aliphatic alcohol and, optionally, at least one polyalkylene glycol: Theat least one hydroxyalkyl cellulose is preferably a hydroxy (C₁ to C₆)alkyl cellulose, such as hydroxypropylcellulose,hydroxypropylmethylcellulose and, especially, hydroxyethylcellulose. Theamount of the at least one hydroxyalkyl cellulose in the present oraldosage form will be determined, inter alia, by the precise rate ofopioid release required. The at least one aliphatic alcohol may be, forexample, lauryl alcohol, myristyl alcohol or stearyl alcohol. Inparticularly preferred embodiments of the present oral dosage form,however, the at least one aliphatic alcohol is cetyl alcohol orcetostearyl alcohol. The amount of the at least one aliphatic alcohol inthe present oral dosage form will be determined, as above, by theprecise rate of opioid release required. It will also depend on whetherat least one polyalkylene glycol is present in or absent from the oraldosage form. In the absence of at least one polyalkylene glycol, theoral dosage form preferably contains between 20% and 50% (by wt) of theat least one aliphatic alcohol. When at least one polyalkylene glycol ispresent in the oral dosage form, then the combined weight of the atleast one aliphatic alcohol and the at least one polyalkylene glycolpreferably constitutes between 20% and 50% (by wt) of the total dosage.

In one embodiment, the ratio of, e.g., the at least one hydroxyalkylcellulose or acrylic resin to the at least one aliphaticalcohol/polyalkylene glycol determines, to a considerable extent, therelease rate of the opioid from the formulation. A ratio of the at leastone hydroxyalkyl cellulose to the at least one aliphaticalcohol/polyalkylene glycol of between 1:2 and 1:4 is preferred, with aratio of between 1:3 and 1:4 being particularly preferred.

The at least one polyalkylene glycol may be, for example, polypropyleneglycol or, which is preferred, polyethylene glycol. The number averagemolecular weight of the at least one poly-alkylene glycol is preferredbetween 1,000 and 15,000 especially between 1,500 and 12,000.

Another suitable controlled release matrix would comprise analkylcellulose (especially ethyl cellulose); a C₁₂ to C₃₆ aliphaticalcohol and, optionally, a polyalkylene glycol.

In another preferred embodiment, the matrix includes a pharmaceuticallyacceptable combination of at least two hydrophobic materials.

In addition to the above ingredients, a controlled release matrix mayalso contain suitable quantities of other materials, e.g. diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art.

Processes for Preparing Matrix-Based Beads

In order to facilitate the preparation of a solid, controlled release,oral dosage form according to this invention, any method of preparing amatrix formulation known to those skilled in the art may be used. Forexample incorporation in the matrix may be effected, for example, by (a)forming granules comprising at least one water soluble hydroxyalkylcellulose and opioid or an opioid salt; (b) mixing the hydroxyalkylcellulose containing granules with at least one C₁₂-C₃₆ aliphaticalcohol; and (c) optionally, compressing and shaping the granules.Preferably, the granules are formed by wet granulating the hydroxyalkylcellulose/opioid with water. In a particularly preferred embodiment ofthis process, the amount of water added during the wet granulation stepis preferably between 1.5 and 5 times, especially between 1.75 and 3.5times, the dry weight of the opioid.

In yet other alternative embodiments, a spheronizing agent, togetherwith the active ingredient can be spheronized to form spheroids.Microcrystalline cellulose is preferred. A suitable microcrystallinecellulose is, for example, the material sold as Avicel PH 101 (TradeMark, FMC Corporation). In such embodiments, in addition to the activeingredient and spheronizing agent, the spheroids may also contain abinder. Suitable binders, such as low viscosity, water soluble polymers,will be well known to those skilled in the pharmaceutical art. However,water soluble hydroxy lower alkyl cellulose, such ashydroxypropylcellulose, are preferred. Additionally (or alternatively)the spheroids may contain a water insoluble polymer, especially anacrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethylacrylate copolymer, or ethyl cellulose. In such embodiments, thesustained release coating will generally include a hydrophobic materialsuch as (a) a wax, either alone or in admixture with a fatty alcohol; or(b) shellac or rein.

Melt Extrusion Matrix

Sustained release matrices can also be prepared via melt-granulation ormelt-extrusion techniques. Generally, melt-granulation. techniquesinvolve melting a normally solid hydrophobic material, e.g. a wax, andincorporating a powdered drug therein. To obtain a sustained releasedosage form, it may be necessary to incorporate an additionalhydrophobic substance, e.g. ethylcellulose or a water-insoluble acrylicpolymer, into the molten wax hydrophobic material. Examples of sustainedrelease formulations prepared via melt-granulation techniques are foundin U.S. Pat. No. 4,861,598, assigned to the Assignee of the presentinvention and hereby incorporated by reference in its entirety.

The additional hydrophobic material may comprise one or morewater-insoluble wax-like thermoplastic substances possibly mixed withone or more wax-like thermoplastic substances being less hydrophobicthan said one or more water-insoluble wax-like substances. In order toachieve constant release, the individual wax-like substances in theformulation should be substantially non-degradable and insoluble ingastrointestinal fluids during the initial release phases. Usefulwater-insoluble wax-like substances may be those with a water-solubilitythat is lower than about 1:5,000 (w/w).

In addition to the above ingredients, a sustained release matrix mayalso contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art, The quantitiesof these additional materials will be sufficient to provide the desiredeffect to the desired formulation. In addition to the above ingredients,a, sustained release matrix incorporating melt-extrudedmultiparticulates may also contain suitable quantities of othermaterials, e.g. diluents, lubricants, binders, granulating aids,colorants, flavorants and glidants that are conventional in thepharmaceutical art in amounts up to about 50% by weight of theparticulate if desired.

Specific examples of pharmaceutically acceptable carriers and excipientsthat may be used to formulate oral dosage forms are described in theHandbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (1986), incorporated by reference herein.

Melt Extrusion Multiparticulates

The preparation of a suitable melt-extruded matrix according to thepresent invention may, for example, include the steps of blending theopioid analgesic, together with at least one hydrophobic material andpreferably the additional hydrophobic material to obtain a homogeneousmixture. The homogeneous mixture is then heated to a temperaturesufficient to at least soften the mixture sufficiently to extrude thesame. The resulting homogeneous mixture is then extruded to formstrands. The extrudate is preferably cooled and cut intomultiparticulates by any means known in the art. The strands are cooledand cut into multiparticulates. The multiparticulates are then dividedinto unit doses. The extrudate preferably has a diameter of from about0.1 to about 5 mm and provides sustained release of the therapeuticallyactive agent for a time period of from about 8 to about 24 hours.

An optional process for preparing the melt extrusions of the presentinvention includes directly metering into an extruder a hydrophobicmaterial, a therapeutically active agent, and an optional binder,heating the homogenous mixture; extruding the homogenous mixture tothereby form strands; cooling the strands containing the homogeneousmixture; cutting the strands into particles having a size from about 0.1mm to about 12 mm; and dividing said particles into unit doses. In thisaspect of the invention, a relatively continuous manufacturing procedureis realized

The diameter of the ex4tider aperture or exit port can also be adjustedto vary the thickness of the extruded strands. Furthermore, the exitpart of the extruder need not be round; it can be oblong, rectangular,etc. The exiting strands can be reduced to particles using a hot wirecutter, guillotine, etc.

The melt extruded multiparticulate system can be, for example, in theform of granules, spheroids or pellets depending upon the extruder exitorifice. For purposes of the present invention, the terms “melt-extrudedmultiparticulate(s)” and “melt-extruded multiparticulate system(s)” and“melt-extruded particles” shall refer to a plurality of units,preferably within a range of similar size and/or shape and containingone or more active agents and one or more excipients, preferablyincluding a hydrophobic material as described herein. In this regard,the melt-extruded multiparticulates will be of a range of from about 0.1to about 12 mm in length and have a diameter of from about 0.1 to about5 mm. In addition, it is to be understood that the melt-extrudedmultiparticulates can be any geometrical shape within this size range.Alternatively, the extrudate may simply be cut into desired lengths anddivided into unit doses of the therapeutically active agent without theneed of a spheronization step.

In one preferred embodiment, oral dosage forms are prepared to includean effective amount of melt-extruded multiparticulates within a capsule.For example, a plurality of the melt-extruded multiparticulates may beplaced in a gelatin capsule in an amount sufficient to provide aneffective sustained release dose when ingested and contacted by gastricfluid.

In another preferred embodiment, a suitable amount of themultiparticulate extrudate is compressed into an oral tablet usingconventional tableting equipment using standard techniques. Techniquesand compositions for making tablets (compressed and molded), capsules(hard and soft gelatin) and pills are also described in Remington'sPharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980),incorporated by reference herein.

In yet another preferred embodiment, the extradate can be shaped intotablets as set forth in U.S. Pat. No. 4,957,681 (Klimesch, et. al.),described in additional detail above and hereby incorporated byreference.

Optionally, the sustained release melt-extruded multiparticulate systemsor tablets can be coated, or the gelatin capsule can be further coated,with a sustained release coating such as the sustained release coatingsdescribed above. Such coatings preferably include a sufficient amount ofhydrophobic material to obtain a weight gain level from about 2 to about30 percent, although the overcoat may be greater depending upon thephysical properties of the particular opioid analgesic compound utilizedand the desired release rate, among other things.

The melt-extruded unit dosage forms of the present invention may furtherinclude combinations of melt-extruded multiparticulates containing oneor more of the therapeutically active agents disclosed above beforebeing encapsulated. Furthermore, the unit dosage forms can also includean amount of an immediate release therapeutically active agent forprompt therapeutic effect. The immediate release therapeutically activeagent may be incorporated, e.g., as separate pellets within a gelatincapsule, or maybe coated on the surface of the multiparticulates afterpreparation of the dosage forms (e.g., controlled release coating ormatrix-based). The unit dosage forms of the present invention may alsocontain a combination of controlled release beads and matrixmultiparticulates to achieve a desired effect.

The sustained release formulations of the present invention preferablyslowly release the therapeutically active agent, e.g., when ingested andexposed to gastric fluids, and then to intestinal fluids. The sustainedrelease profile of the melt-extruded formulations of the invention canbe altered, for example, by varying the amount of retardant, i.e.,hydrophobic material, by varying the amount of plasticizer relative tohydrophobic material, by the inclusion of additional ingredients orexcipients, by altering the method of manufacture, etc.

In other embodiments of the invention, the melt extruded material isprepared without the inclusion of the therapeutically active agent,which is added thereafter to the extrudate, Such formulations typicallywill have the therapeutically active agent blended together with theextruded matrix material, and then the mixture would be tableted inorder to provide a slow release formulation. Such formulations may beadvantageous, for example, when the therapeutically active agentincluded in the formulation is sensitive to temperatures needed forsawing the hydrophobic material and/or the retardant material.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The following examples illustrate various aspects of the presentinvention. They are riot to be construed to limit the claims in anymanner whatsoever.

A direct comparison of the competitive antagonist properties ofnaltrexone following its coadministration with various opioid agonistshas not been undertaken previous to the present invention, to theknowledge of the inventors. However, dose-ranging studies have beenconducted evaluating the opioid antagonist properties in subjectsreceiving either heroin or morphine challenges. In general,preadministration, of naltrexone 50 mg 24 hours prior to 26 mg ofintravenous heroin challenge completely blocked or attenuated the opioidagonist effects. See, Gonzalez J P, Brogden R N, “Naltrexone: A Reviewof its Pharmacodynamic and Pharmacokinetic Properties and TherapeuticEfficacy in the Management of Opioid Dependence.” Drugs 1988;35:192-213; Resnick R R, Valavka. J, Freedman A M, Thomas M. “Studies ofEN-1639A (Naltrexone): A New Narcotic Antagonist.” Am. J. Psychiatry1974; 131:646-650, both of which are hereby incorporated by reference.

Example 1

In Example 1, a randomized, single-blind, placebo-controlled,single-dose, four-way crossover study was conducted which assessedwhether naltrexone oral solution 6.4 mg would block opioid agonistproperties of hydrocodone 15 mg in 6 normal, healthy, female volunteers.The study population included only females because previous observationshave indicated that females have an increased sensitivity to the opioidagonist effects as compared to males, The four treatments were HYIR/APAP(2 tablets of hydrocodone 7.5 and acetaminophen 750 mg, Vicodin® ES′)and naltrexone oral solution 3.2 mg, HYIR/APAP (2×7.5 mg) and naltrexoneoral solution 6.4 mg, HYIR comparator tablets (2×750 mg Trilisate®tablets) and naltrexone oral solution (placebo), and HYIR/APAP (2tablets of Vicodin ES®) and naltrexone oral solution (placebo). Alltreatments wore administered under fasted conditions. A 48-hour washoutperiod occurred between doses. Subjects were randomly assigned to fourtreatment sequences of the four treatment groups. Subjects reported tothe testing facility the evening prior to the first dose and remainedconfined there until completion of the 24-hour post-dose assessment ofthe last dose. Safety measurements consisted of reports of adverseevents, vital signs, abnormal laboratory values, abnormal physicalexamination and ECG results. Pharmacodynamic parameters (pupil size andModified Specific Drug Effect Questionnaire) were also assessed.

Test Treatments

The four treatments were as follows:

Hydrocodone immediate-release tablets (2×7.5 mg) and naltrexone oralsolution 3.2 mg. Hydrocodone immediate-release tablets (2×7.5 mg) andnaltrexone oral solution 6.4 mg. Hydrocodone immediate-releasecomparator tablets and placebo naltrexone oral solution. Placebohydrocodone immediate-release tablets (2×7.5 mg) and placebo naltrexoneoral solution.

Test Products

The products evaluated in this study include Vicodin ES® (hydrocodonebitartrate 7.5 mg and acetaminophen 750 mg; Knoll Pharmaceuticals),Trilisate® (choline magnesium trisalicylate 750 mg, Purdue Frederick)which served as the comparator, and naltrexone powder. Vicodin ES® wasselected as the active treatment since the acetaminophen portion withinthis product is expected to have no effect on the central nervous systemor pupillary measurement. Trilisate was selected to be used as the“comparator” since its physical appearance is similar to Vicodin ES® andit has no effect on the central nervous system or pupillary measurement.Naltrexone powder formulation was selected rather than the commerciallyapproved tablet formulation (Revia® 50 mg tablets, DuPont) to improvethe overall precision in the preparation of the oral solution. Anon-site research pharmacist reconstituted the oral solution from thenaltrexone powder in a sterile environment utilizing appropriatepharmaceutical techniques. Naltrexone powder (Mallinckrodt Chemical) wasused to formulate the naltrexone solution. Individual stock solutions ofnaltrexone were prepared using a modification of the method proposed byTsang and Holtsman. Tsang B K, Holtsman R. “Room Temperature Stabilityof Lipid Naltrexone.” Anesthesiology 1995:83:A864, hereby incorporatedby reference Immediately prior (<60 minutes) to each dosing period, analtrexone stock solution was prepared by weighing out 32 mg and 64 mgof naltrexone powder. Each of these portions was dissolved in 50 mL ofdistilled water and 50 mL of simple syrup, NF for a final volume of 100mL. The concentration of the final solutions was 0.32 mg/mL (32 mg/100mL) and 0.64 mg/mL (64 mg/100 mL), respectively. These concentrationsallowed the same volume (10 mL) of naltrexone oral solution to beadministered during each dosing period. The naltrexone oral solutionplacebo was prepared in the same vehicle as the active solution. Theaddition of a bittering agent, Bitterguard (denatonium benzoate, NF)powder, was added to provide a taste similar to the active solution.

Pharmacodynamic Measurements

a. Pupil Size—Measured by Pupillometry.

Pupillary diameter measurements wore made with the Polaroid CU-5 camerawith a 75 mm lens and built-in electronic ring flash using Polacolor ER669 instant pack film.12. This ‘method has become accepted as a safe andaccurate way to study pupils and is commonly regarded as being secondonly to the infrared television pupillometric technique (a moreversatile and sophisticated, but also much more expensive andcumbersome, method). The Polaroid CU-5 method is said to be accurate towithin 0.1 millimeters. See, Czarnecki JS, Pulley S F, Thompson H S.“The Use of Photography in the Clinical Evaluation of Unequal Pupils.”Canad J Ophthal 1979; 14:297-302; hereby incorporated by reference.

Pupil diameters were measured as follows: The camera was modified bycovering two small sections of the ring flash at 3 and 9 o'clock so thatthe corneal reflection of the flash does not obscure the horizontalpapillary margin. The camera was centered in front of the subject's facewith 3 inch frame against the lateral orbital rims and the eyesoccupying the very top of the field (to minimize upgaze). The subjectwas asked to look just over the camera body and to fixate on anon-accommodative target in the distance, thereby minimizing the nearreflex. With the volunteer fixing in the distance, the photo was taken.All photographs were taken in constant ambient light. The papillarylatency was such that the flash will not affect papillary diameter.Tonic constriction of the pupil after the flash does occur, but is ofshort duration; therefore, it did not interfere with the measurementsnecessary for this trial. See, Smith S A, Dewhist R R. “A SingleDiagnostic Test for Papillary Abnormality in Diabetic AutonomicNeuropathy.” Diabetic Medicine 1988; 3:38-41; hereby incorporated byreference. Development of the print for the recommended length of time(approximately one (1) minute, varying with ambient temperature) willproduce a one-to-one photograph of the volunteer's midface, with thepupils at the top of the print. Horizontal papillary diameter is thenmeasured using a simple plus magnifier with a built-in reticulecalibrated to 0.1. millimeter. Only the left eye was used to measurepupillary effects at each time period specified in the protocol.

b. A Modified Specific Drag Effect Questionnaire.

The questionnaire is a modification of the 22 item questionnaire used byJasinski and Preston. See, Jasinski D R. “Assessment of the AbusePotential of Morphine-Like Drugs (methods used in man).” In: DrugAddiction I (Martin; W. R., ed.), 1997:197-258. Springer-Verlag, NewYork; Preson K L, Jasinski D R, Testa M. “Abuse Potential andPharmacological Comparison of Tramadol and Morphine.” Drug and AlcoholDependence 1991; 27:7-17; both of which are hereby incorporated byreference. The present questionnaire consisted of 10 items rated by thesubject 10 minutes prior to blood sampling. The item is related to signsof opiate agonist drugs and was as follows:

Subject questions: 1) do you feel any effects from the drugs?, 2) doesyour skin feel itchy?, 3) do you feel relaxed?, 4) do you feel sleepy?,5) do you feel drunk?, 6) do you feel nervous?, 7) do you feel full ofenergy?, 8) do you feel you need to talk?, 9) do you feel sick to yourstomach?, 10) do you feel dizzy? The subject then rated the item byplacing a vertical mark along a 100 mm visual analog scale (VAS)anchored on one end by “not at all” and at the other end by “an awfullot”.

Pupil size of the left eye made at baseline (within 30 minutes prior todosing), and at 0.5, 1, 2, 4, 6, 9 and 12 hours post-dose was measured,and the subject rated drug effect scores as measured on a visual analogscale for the Modified Specified Drug Effect Questionnaire (“MSDEQ”) atbaseline, and at 0.5, 1, 2, 4, 6, 9 and 12 hours post-dose.

Separate graphs for the eleven responses (MSDEQ questions and pupillarydiameter measurement) versus naltrexone dose were visually andstatistically examined to determine the nominally effective dose ofnaltrexone in combination with the hydrocodone dose used in the study.

The adverse events reported were those commonly associated with theadministration of opioid analgesics, and most were classified as “mild”.No serious adverse events or deaths occurred, and no patients werediscontinued from the study secondary to adverse events.

Results are presented in FIGS. 1 and 2.

FIG. 1 shows the naltrexone antagonism of hydrocodone-induced. VAS(Visual Analog scale) “drug effect”. This refers to the first questionof the Modified Specific Drug Effect Questionnaire which asked thesubjects “do you feel any effects of the drug?”. The results suggestthat there is a dose-response effect for naltrexone; increasing the doseof naltrexone decreased the VAS “drag effect” of hydrocodone. The 6.4-mgdose of naltrexone antagonized the effects of a 15-mg dose ofhydrocodone to a greater degree than the 32-mg naltrexone dose. Theopioid effect of hydrocodone was not completely blocked by the 6.4-mgnaltrexone dose.

FIG. 2 shows the naltrexone antagonism of hydrocodone-induced papillaryconstriction; These results also suggest a dose-response effect fornaltrexone; increasing the dose of naltrexone caused less papillaryconstriction in subjects who had received hydrocodone 15 mg, The 6.4-mgnaltrexone dose antagonized hydrocodone-induced papillary constrictionto a greater degree than the 3.2-mg naltrexone dose. The papillaryconstriction of hydrocodone was not completely blocked by the 6.4-mgnaltrexone dose. The least amount of pupillary constriction occurred inthe placebo-group, The hydrocodone plus naltrexone placebo-groupexperienced the most papillary constriction, and therefore, had thelowest measurements for pupillary diameter.

Example 2

In Example 2, a ten period, randomized, crossover, single-blind studyevaluating the ratio of oral naltrexone to oral hydrocodone that wouldnominally minimize the opioid agonist effects was conducted in normal,healthy, female volunteers. Twenty-one subjects enrolled in the study,and 16 completed the study. The ten treatments included HYIR/APAP (2tablets of hydrocodone 7.5 and acetaminophen 750 mg per tablet, VicodinES® with the following doses of naltrexone oral solution: 0.4 mg/10 mL,0.8 mg/10 mL, 1.6 mg/10 mL, 3.2 mg/10 mL, 4.8 mg/10 mL, 6.4 mg/10 mL,9.6 mg/10 mL, 12.8 mg/10 mL, and placebo naltrexone oral solution, aswell as hydrocodone immediate-release comparator tablets (2×750 mgTrilisate® tablets) with placebo naltrexone oral solution. Alltreatments were administered under fasted conditions. A 48-hour washoutperiod occurred between doses. Subjects were randomly assigned to tentreatment sequences of the ten treatment groups. Subjects reported tothe testing facility the evening prior to the first dose and remainedconfined there until completion of the 24-hour post-dose assessment ofthe last dose. Safety measurements consisted of reports of adverseevents, vital signs, abnormal laboratory values, abnormal physicalexamination and ECG results. Plasma hydrocodone, naltrexone and6-P-naltrexol levels were obtained, and pharmacokinetic values will becalculated and analyzed. Pharmacodynamic parameters (pupil size andModified Specific Drug Effect Questionnaire) were also assessed.

Dosing Regimen

The dosing regimen was as follows:

Hydrocodone immediate-release comparator (placebo) tablets wereadministered with 10 mL naltrexone oral solution (placebo) atapproximately 08:00 on the dosing day in Periods 1 through 10 followingan 8-hour fast. The fast continued for an additional four (4) hourspost-dose;Hydrocodone immediate-release tablets (2×7.5 mg) were administered with10 mL naltrexone oral solution (placebo) at approximately 08:00 on thedosing day in Periods 1 through 10 following an 8-hour fast. The fastcontinued for an additional four (4) hours post-dose;Hydrocodone immediate-release tablets (2×7.5 mg) were administered with10 mL naltrexone oral solution (0.4 mg) at approximately 08:00 on thedosing day in Periods I through 10 following an. 8-hour fast, The fastcontinued for an additional four (4) hours post-dose;Hydrocodone immediate-release tablets (2×7.5 mg) were administered with10 mL naltrexone oral solution (0.8 mg) at approximately 08:00 on thedosing day in Periods I through 10 following an 8-boar fast. The fastcontinued for an additional four (4) hours post-dose;Hydrocodone immediate-release tablets (2×7.5 mg) were administered with10 mL naltrexone oral solution (1.6 mg) at approximately 08:00 on thedosing day in Periods 1 through 10 following an 8-hour fast. The fastcontinued for an additional four (4) hours post-dose;Hydrocodone immediate-release tablets (2×7.5 mg) were administered with10 mL naltrexone oral solution (3.2 mg) at approximately 08:00 on thedosing day in Periods 1 through 10 following an 8-hour fast. The fastcontinued for an additional. four (4) hours post-dose;Hydrocodone immediate-release tablets (2×7.5 mg) were administered with10 mL, naltrexone oral solution (4.8 mg) at approximately 08:00 on thedosing day in Periods 1 through 10 following an 8-hour fast. The fastcontinued for an additional four (4) hours. post-dose;Hydrocodone immediate-release tablets (2×7.5 mg) were administered with10 mL naltrexone oral solution (6.4 mg) at approximately 08:00 on thedosing day in Periods 1 through 10 following an 8-hour fast. The fastcontinued for an additional four (4) hours post-dose;Hydrocodone immediate-release tablets (2×7.5 mg) were administered with10 mL, naltrexone oral solution (9.6 mg) at approximately 08:00 on thedosing day in Periods 1 through 10 following an 8-hour fast. The fastcontinued for an additional four (4) hours post-dose;Hydrocodone immediate-release tablets (2×7.5 mg) were administered with10 mL naltrexone oral solution (12.8 mg) at approximately 08:00 on thedosing day in Periods I through 10 following an 8-hour fast. The fastcontinued for an additional four (4) hours post-dose.

The subjects observed an 8 hour fast preceding and fasted for four (4)hours following each dose administration of the assigned drug on eachdosing day. A baseline blood sample (for Plasma Hydrocodone, Naltrexoneand 6-β-naltrexol) was obtained prior to dosing (within 30 minutes)administration of initial dose (0 hr) and at 0.5, 1, 2, 4, 6 and 9 hourspost-dose. All samples were collected within ±2 minute of the scheduledtime. Measurements of the following pharmacodynamic parameters were madejust prior to blood sampling at baseline (within 30 minutes prior todosing), and at 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr and 9 hr post-dose.

Immediately prior to each dosing period, 8 individual naltrexone stocksolutions were prepared by weighing out 4, 8, 16, 32, 48, 64, 96, and128 mg of naltrexone powder. Each of these portions were dissolved in 50ml of distilled water and 50 ml of simple syrup. The final solution was100 mL at a concentration of 0.04, 0.08, 0.16, 0.32, 0.48, 0.96, and1.28 mg/mL. These concentrations allowed the same volume (10 ml) ofnaltrexone solution to be administered during each dosing period. Thenaltrexone placebo solution was be prepared in the same vehicles as theactive solution. The addition of a buttering agent, Bitterguard Powder(denatoniurn benzoate), was added to provide a taste similar to theactive solution.

Pharmacodynamic Measurements

Pharmacodynamic measurements for Example 2 were obtained in accordancewith the procedures set forth With respect to Example 1 above.

The mean “drug effect” VAS score and pupil diameter over time for eachof the treatments are presented in FIGS. 3 and 4, respectively. Ingeneral, the single-dose administration of hydrocodone immediaterelease/acetaminophen (“HYIR/APAP”) with increasing doses of naltrexone(range 0 mg-12.8 mg) resulted in an overall decrease in “drug effect”VAS score and decrease in pupillary constriction. FIGS. 5 and 6 presentthe corresponding mean maximum “drug effect” VAS score (±95% CI) andmean minimum pupil diameter (±95% CI) versus the log from each of thenaltrexone doses. Both figures suggest a dose-response relationship withthe pupil effect demonstrating a greater dose-response relationshipcompared to the “drug effect” VAS response.

The results suggest that even with the inclusion of 0.4 mg naltrexone,there was a diminution of pharmacologic effects of the dose ofhydrocodone. Approximately 0.4 mg of naltrexone minimally antagonizedthe 15 mg hydrocodone dose. Dosages above naltrexone 0.4 mg began toshow increasing diminution of the effect of the hydrocodone dose.

The adverse events reported were those commonly associated with theadministration of opioid analgesics, and most were classified as “mild”.A total of five subjects ( 5/21) discontinued the study. Three subjectsdiscontinued due to adverse events. Two of these subjects experiencedadverse events which were classified as non-serious. One subjectdeveloped anemia which was classified as serious, and required irontherapy. Another two Subjects were discontinued from the study becausetheir physicians felt there was information in their medical historythat did not make it possible for them to participate. No deathsoccurred in this study.

In general, the single-dose administration of 15 mg hydrocodoneimmediate-release tablets with increasing doses of naltrexone oralsolution (range 0 mg-12.8 mg) resulted in an overall decrease in “drugeffect” VAS score and an increase in pupil diameter.

Example 3

Example 3 presents the results of a study evaluating precipitatedwithdrawal in morphine dependent volunteers receiving hydrocodoneimmediate-release tablets and naltrexone oral solution. The study was asingle-blind, single-dose, placebo-controlled naltrexone dose ascendingstudy in subjects physically dependent on opioids. The experimentalsubjects (5) were opioid-dependent as determined by Narcan Challenge,Addiction severity Index scores, physical examination, observation andurine drug screen results, and were not currently seeking treatment fortheir addiction. To evaluate precipitated withdrawal following thecoadministration of hydrocodone immediate release and naltrexone, a 30mg dose of hydrocodone immediate release was selected to simulate a doselevel used by individuals who abuse hydrocodone. This is also a dosewhich is considered to be equianalgesic to other commonly used opioidsin opioid naive patients. The relative analgesic potency of hydrocodoneis believed to be similar to that of oxycodone and about two times thatof oral morphine.

Test Treatments

The treatments were as follows:

Hydrocodone/acetaminoplien immediate-release (HYIR/APAP) tablets 30 mg(Lortab® 3×10 mg) and increasing doses of naltrexone oral solutions 0,0.25 mg, 0.5 mg, 1.0 mg and 2.0 mg. Hydrocodone/acetaminophenimmediate-release (HYIR/APAP) tablets 30 mg (Lortab® 3×10 mg) andnaltrexone placebo oral solution. The naltrexone oral solution andplacebo solution were prepared in accordance with Examples 1-2.

The subjects were stabilized for 5 days by administering 15 mg morphinesulphate i.m. at regular intervals: 6 and 10 A.M., and 4 and 10 P.M.daily. Fifteen mg morphine sulphate i.m. is equivalent to 30 mghydrocodone given orally. The study medications were administered afterstabilization at 10 AM on study medication dosing days, and observationswere made over the next six hours. After six hours, if precipitatedwithdrawal was not observed, the administration of morphine sulfate 15mg intramuscularly resumed with the 4 PM dose. The subjects werestabilized 48 hours before the next study drug administration. Followingeach treatment (1-4), if precipitated withdrawal was not observed, thesubject received study medication from the next treatment in thefollowing ascending order:

Treatment No. 1: HYIR/APAP tablets 30 mg (Lortab® 3×10 mg) administeredwith placebo naltrexone (10 mL oral solution at approximately 10:00 onthe dosing day following an 8-hour fast. The fast continued for anadditional four (4) hours post-dose.Treatment No. 2: HYIR/APAP tablets 30 mg (Lortab® 3×10 mg) administeredwith 0.25 mg naltrexone (10 mL) oral solution at approximately 10:00 onthe dosing day following an 8-hour fast. The fast continued for anadditional four (4) hours post-dose.Treatment No 3: HYIR/APAP tablets 30 mg (Lortab® 3×10 mg) administeredwith 0.5 mg naltrexone (10 mL) oral solution at approximately 10:00 onthe dosing day following an 8-hour fast. The fast continued for anadditional four (4) hours post-dose.Treatment No. 4: HYIR/APAP tablets 30 mg (Lortab® 3×10 mg) administeredwith 1.0 mg naltrexone (10 mL) oral solution at approximately 10:00 onthe dosing day following an 8-hour fast. The fast continued for anadditional four (4) hours post-dose.Treatment No. 5: HYIR/APAP tablets 30 mg (Lortab® 3×10 mg) administeredwith 2:0 mg naltrexone (10 mL) oral solution at approximately 10:00 onthe dosing day following an 8-hour fast. The fast continued for anadditional four (4) hours post-dose.

Blood samples were collected at 0.5 hours pre-dose, and at 0.5, 1, 2, 4and 6 hours post-dose. Pupil diameter measurements were obtained using aPupilscan pupillometer and recorded in millimeters to the nearestmillimeter. There was a 48 hour washout period following each testperiod. Four subjects completed the study, one subject was terminated.The effect of naltrexone was a slight abstinence (symptoms ofwithdrawal) at 1 and 2 mg.

The protocol was amended and twelve experimental subjects participatedin the protocol, which was identical to the study outlined above exceptfor the increased ratio of naltrexone. Naltrexone doses in the revisedprotocol were 0, 1, 2, 4 and 8 mg. Eight of the experimental subjectscompleted the study, while four withdrew.

Vital signs for each subject were monitored, and subjects were monitoredfor signs and symptoms of opioid withdrawal. Withdrawal signs includestuffiness or running nose, tearing, yawning, sweating, tremors,vomiting, piloerection, mydriasis, irritability and restlessness.Withdrawal symptoms include feeling of temperature change, joint, boneor muscle pain, abdominal cramps, skin crawling, nausea, and thesubject's reporting the subjective experience of the aforementionedsymptoms.

To provide a measure of the subjective experience of the drugcombination, the subjects answered questionnaires throughout the studyperiod. The responses to questions were graded on the Visual AnalogScale as described in Example I. The subjective experiences that wereassessed were as follows: like/dislike of the drug, ability to perceivedrug effect, sweating, restlessness, shakiness, watery eyes, gooseflesh,stomach upset, nasal congestion, sleepiness, cold, hot, muscle ache,tenseness or relaxation, confusion, fearfulness, irritability,talkativeness, sensations of withdrawal, sensations of sickness. Thesubjects were also observed for the following symptoms: yawning,scratching, relaxed, nasal congestion, irritability, withdrawal. Inaddition, blood pressure, pulse rate, respiration rate, pupil size andbody temperature were monitored.

The data for five of the subjects are presented below. FIGS. 7A-Cillustrate the mean scores for subjective perception of hydrocodone fromthe questionnaires, plotted as a function of time post administrationand as a function of naltrexone dose. FIG. 7A illustrates the subjects'ability to feel the effect of hydrocodone in the presence of varyingamounts of naltrexone. FIGS. 7B and 7C illustrate the subjects'favorable or unfavorable subjective experiences of hydrocodone in thepresence of varying amounts of naltrexone, respectively.

FIGS. 8A and B illustrate the mean scores for subjective perception ofthe effects of hydrocodone, plotted as a function of time postadministration and as a function of naltrexone dose. FIG. 8A illustratesthe subjects' perception of withdrawal from the effect of hydrocodone inthe presence of varying amounts of naltrexone. FIG. 8B illustrates thesubjective experience of illness in the presence of varying amounts ofnaltrexone. FIG. 9A illustrates the effect on pupil size of hydrocodonein the presence of varying amounts of naltrexone. FIG. 9B illustratesthe apparent extent of withdrawal from the effect of hydrocodone in thepresence of varying amounts of naltrexone, from the perspective of theobserver.

FIGS. 10A-C present the areas under the curves presented in FIGS. 7A-C,integrated over the 6 hour observation period, as a function ofnaltrexone dose, and the 95% confidence levels for the placebo responseof naltrexone (30 mg hydrocodone, 0 mg naltrexone). FIG. 10A illustratesthat up to 8 mg naltrexone does not abolish the ability of the subjectto perceive the effect of hydrocodone: the experimentally determined AUC(0 to 6 hours) observed for each naltrexone dose lies wholly within the95% confidence limits for the naltrexone placebo response. FIG. 10Billustrates the AUC (0 to 6 hours) for the subjects' favorablesubjective experience to hydrocodone as a function of naltrexone dose.FIG. 10B illustrates that the favorable subjective experience isdecreased for >1 mg naltrexone, that is, the experimentally determinedAUC (0 to 6 heirs) decreased below the 95% confidence limits fornaltrexone placebo at approximately 1 mg naltrexone. FIG. 10Cillustrates that the unfavorable subjective experience is increasedfor >1 mg naltrexone, that is, the experimentally determined AUC (0 to 6hours) increased above the 95% confidence limits for naltrexone placeboat approximately 1 mg naltrexone.

FIGS. 11A-C present the areas under the curves presented in FIGS. 8A-Band FIG. 9A, integrated over the 6 hour observation period, as afunction of naltrexone dose, and the 95% confidence levels for theplacebo response of naltrexone (30 mg hydrocodone, 0 mg naltrexone).FIG. 11A illustrates the AUC (0 to 6 hours) for the subjectiveexperience of illness in the presence of varying amounts of naltrexone.FIG. 11A demonstrates that doses of naltrexone greater thanapproximately 0.75 mg result in the subjective experience of withdrawal:the experimentally determined AUC (0 to 6 hours) observed in FIG. 8A foreach naltrexone dose increases above the 95% confidence limits for thenaltrexone placebo response at approximately 0.75 mg naltrexone. FIG.11B illustrates the AUC (0 to 6 hours) for the subjects' perception ofillness in the presence of varying amounts of naltrexone. FIG. 11Bdemonstrates that doses of naltrexone greater than approximately 0.75 mgresult in the subjective experience of illness: the experimentallydetermined AUC (0 to 6 hours) observed in FIG. 8B for each naltrexonedose increases above the 95% confidence limits for the naltrexoneplacebo response at approximately 0.75 mg naltrexone. FIG. 11Cillustrates the AUC (0 to 6 hours) of the experimentally determinedchange in pupil size as a function of naltrexone dose. FIG. 11Cdemonstrates that up to 8 mg naltrexone does not abolish the miosiseffect of hydrocodone: the experimentally determined AUC (0 to 6 hours)observed in FIG. 9A for each naltrexone dose lies wholly within the 95%confidence limits for the naltrexone placebo response.

The clinical study demonstrates that hydrocodone, in combination withnaltrexone, has an onset of <0.5 hours, peaks within 0.5 to 1 hour andis markedly diminished within 3 to 4 hours. A shallow dose-responsecurve was observed. The addition of naltrexone decreased the favorablesubjective experience of hydrocodone, increased the subjectiveexperience of dislike for hydrocodone and increased the subjectiveexperience of sickness and withdrawal from the effects of hydrocodone.These experiences are clearly aversive.

While the invention has been described and illustrated with reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that obvious modifications can be made herein withoutdeparting from the spirit and scope of the invention. Such variationsare contemplated to be within the scope of the appended claims.

1-35. (canceled)
 36. An immediate release oral dosage form, comprising:an orally therapeutically effective dose of an opioid agonist selectedfrom buprenorphine and pharmaceutically acceptable salts thereof; and anopioid antagonist selected from naltrexone, naloxone, nalmephene,cyclazocine, levallorphan, and mixtures thereof, and pharmaceuticallyacceptable salts thereof; said dosage form having a ratio of opioidantagonist to opioid agonist that provides a combination product whichis therapeutically effective when the combination is administeredorally, but which (i) is aversive in physically dependent human subjectswhen orally abused at a higher dose than said therapeutically effectivedose; and (ii) maintains a therapeutic effect but does not increasetherapeutic efficacy of said opioid agonist relative to the sametherapeutic dose of opioid agonist when administered to human patientswithout said opioid antagonist.
 37. (canceled)
 38. The oral dosage formof claim 36, further comprising an additional non-opioid drug selectedfrom the group consisting of an NSAID, a COX-2 inhibitor, acetaminophen,aspirin, an NMDA receptor antagonist, a drug that blocks a majorintracellular consequence of NMDA-receptor activation, an antitussive,an expectorant, a decongestant, and an antihistamine and mixturesthereof.
 39. The oral dosage form of claim 36, further comprising one ormore pharmaceutically acceptable inert excipients.
 40. The oral dosageform of claim 36, wherein said opioid antagonist is naloxone or apharmaceutically acceptable salt thereof.
 41. The oral dosage form ofclaim 40, wherein the buprenorphine or pharmaceutically acceptable saltthereof is present in the dosage form in an amount that is equianalgesicto about 8 mg to about 50 mg hydrocodone or a pharmaceuticallyacceptable salt thereof.
 42. The oral dosage form of claim 40, whereinthe buprenorphine or pharmaceutically acceptable salt thereof is presentin the dosage form in an amount that is equianalgesic to about 2 mg toabout 64 mg hydromorphone hydrochloride.
 43. The oral dosage form ofclaim 40, wherein the buprenorphine or pharmaceutically acceptable saltthereof is present in the dosage form in an amount that is equianalgesicto about 2.5 mg to about 800 mg morphine or a pharmaceuticallyacceptable salt thereof.
 44. The oral dosage form of claim 40, whereinthe buprenorphine or pharmaceutically acceptable salt thereof is presentin the dosage form in an amount that is equianalgesic to about 2.5 mg toabout 800 mg oxycodone or a pharmaceutically acceptable salt thereof.45. The oral dosage form of claim 40, wherein the buprenorphine orpharmaceutically acceptable salt thereof is present in the dosage formin an amount that is equianalgesic to about 25 mg to about 800 mgtramadol or a pharmaceutically acceptable salt thereof.
 46. (canceled)47. The oral dosage form of claim 40, wherein the combination isaversive in physically dependent human subjects when orally abused atabout 2-3 times said therapeutically effective dose. 48-51. (canceled)52. The oral dosage form of claim 40, wherein the dosage form compriseshydroxypropylmethylcellulose.
 53. The oral dosage form of claim 40,wherein the dosage form comprises polyethylene glycol.
 54. The oraldosage form of claim 40, wherein the dosage form includes acarbohydrate.
 55. The oral dosage form of claim 40, wherein the dosageform is in the form of an oral suppository.
 56. A method of reducingoral abuse of an oral opioid formulation comprising administering theoral dosage form of claim 36 to a subject in need thereof.
 57. Themethod of claim 56, wherein said opioid antagonist is naloxone or apharmaceutically acceptable salt thereof.
 58. The method of claim 57,wherein the buprenorphine or pharmaceutically acceptable salt thereof ispresent in the dosage form in an amount that is equianalgesic to about2.5 mg to about 800 mg morphine or a pharmaceutically acceptable saltthereof.
 59. The method of claim 57, wherein the buprenorphine orpharmaceutically acceptable salt thereof is present in the dosage formin an amount that is equianalgesic to about 2.5 mg to about 800 mgoxycodone or a pharmaceutically acceptable salt thereof. 60-62.(canceled)
 63. The method of claim 57, wherein the dosage form compriseshydroxypropylmethylcellulose.
 64. The method of claim 57, wherein thedosage form comprises polyethylene glycol.
 65. The method of claim 57,wherein the dosage form is in the form of an oral suppository.
 66. Themethod of claim 57, wherein the dosage form is in the form of a buccaltablet.
 67. The method of claim 57, wherein the dosage form furthercomprises an additional non-opioid drug selected from the groupconsisting of an NSAID, a COX-2 inhibitor, acetaminophen, aspirin, anNMDA receptor antagonist, a drug that blocks a major intracellularconsequence of NMDA-receptor activation, an antitussive, an expectorant,a decongestant, and an antihistamine and mixtures thereof.
 68. Themethod of claim 57, wherein the dosage form further comprises one ormore pharmaceutically acceptable inert excipients.
 69. The method ofclaim 57, wherein the buprenorphine or pharmaceutically acceptable saltthereof is present in the dosage form in an amount that is equianalgesicto about 8 mg to about 50 mg hydrocodone or a pharmaceuticallyacceptable salt thereof.
 70. The method of claim 57, wherein thebuprenorphine or pharmaceutically acceptable salt thereof is present inthe dosage form in an amount that is equianalgesic to about 2 mg toabout 64 mg hydromorphone hydrochloride.
 71. The method of claim 57,wherein the buprenorphine or pharmaceutically acceptable salt thereof ispresent in the dosage form in an amount that is equianalgesic to about25 mg to about 800 mg tramadol or a pharmaceutically acceptable saltthereof.
 72. The method of claim 57, wherein the combination is aversivein physically dependent human subjects when orally abused at about 2-3times said therapeutically effective dose.
 73. The method of claim 57,wherein the dosage form includes a carbohydrate.
 74. The oral dosageform of claim 40, wherein the dosage form is in the form of a buccaltablet.